Anti-respiratory syncytial virus antibodies, and methods of their generation and use

ABSTRACT

Anti-RSV antibodies with neutralizing potency against RSV subtype A and RSV subtype B are provided, as well as methods for their identification, isolation, generation, and methods for their preparation and use are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional Patent Application number 62/411,500, filed Oct. 21, 2016, the entire contents of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 20, 2017, is named “2009186_0217_SL.TXT” and is 860,021 bytes in size.

FIELD OF THE INVENTION

The invention relates, inter alia, to anti-Respiratory Syncytial Virus (RSV) antibodies and functional fragments thereof, and methods and reagents for their preparation and use.

BACKGROUND OF THE INVENTION

All references cited herein, including without limitation patents, patent appliciaotns, and non-patent references and publications referenced throughout are hereby expressly incorporated by reference in their entireties for all purposes.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly, is the leading cause of infant hospitalization in the United States and accounts for an estimated 64 million infections and 160,000 deaths world-wide each year. However, despite decades of research, the development of a safe and effective vaccines or therapeutic and/or prophylactic antibodies against RSV has remained elusive, highlighting the need for novel strategies that induce or provide protective immune responses. (1-3). Indeed, to date there are currently no approved RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab (marketed as Synagis®) is restricted to high-risk infants in part due to its modest efficacy.

Certain populations of children are at risk for developing an RSV infection and these include preterm infants (Hall et al., 1979, New Engl. J. Med. 300:393-396), children with congenital malformations of the airway, children with bronchopulmonary dysplasia (Groothuis et al., 1988, Pediatrics 82:199-203), children with congenital heart disease (MacDonald et al., New Engl. J. Med. 307:397-400), and children with congenital or acquired immunodeficiency (Ogra et al., 1988, Pediatr. Infect. Dis. J. 7:246-249; and Pohl et al., 1992, J. Infect. Dis. 165:166-169), and cystic fibrosis (Abman et al., 1988, J. Pediatr. 1 13:826-830).

RSV can infect the adult population as well. In this population, RSV causes primarily an upper respiratory tract disease, although elderly patients may be at greater risk for a serious infection and pneumonia (Evans, A. S., eds., 1989, Viral Infections of Humans. Epidemiology and Control, 3^(rd) ed., Plenum Medical Book, New York at pages 525-544), as well as adults who are immunosuppressed, particularly bone marrow transplant patients (Hertz et al., 1989, Medicine 68:269-281). Other at risk patients include those suffering from congestive heart failure and those suffering from chronic obstructive pulmonary disease (ie. COPD). There have also been reports of epidemics among nursing home patients and institutionalized young adults (Falsey, A. R., 1991, Infect. Control Hosp. Epidemiol. 12:602-608; and Garvie et al., 1980, Br. Med. J. 281:1253-1254).

While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2^(nd) ed., Vol. 1, Raven Press, New York at pages 1045-1072).

Similar to other pneumoviruses, RSV expresses two major surface glycoproteins: the fusion protein (F) and the attachment protein (G). Although both have been shown to induce protective neutralizing antibody responses, F is less genetically variable than G, is absolutely required for infection, and is the target for the majority of neutralizing activity in human serum (4-8). RSV F is also the target of the monoclonal antibody palivizumab, which is used to passively protect high-risk infants from severe disease (9). Consequently, the RSV F protein is considered to be a highly attractive target for vaccines and antibody-based therapies.

The mature RSV F glycoprotein initially exists in a metastable prefusion conformation (10), before undergoing a conformational change that leads to insertion of the hydrophobic fusion peptide into the host-cell membrane. Subsequent refolding of F into a stable, elongated postfusion conformation (postF) (11, 12) results in fusion of the viral and host-cell membranes. Due to its inherent instability, the preF protein has the propensity to prematurely trigger into postF, both in solution and on the viral surface (13). Recently, stabilization of preF has been achieved by protein engineering (14, 15), and stabilized preF has been shown to induce higher titers of neutralizing antibodies than postF in animal models (15).

Despite the importance of neutralizing antibodies in protection against severe RSV disease, our understanding of the human antibody response to RSV has been limited to studies of human sera and a small number of RSV-specific human monoclonal antibodies (16-19). The epitopes recognized by these human antibodies, as well as several murine antibodies, have defined at least four ‘antigenic sites’ on RSV F (1, 10, 16, 18-20) (see also, e.g., Table 1). Three of these sites—I, II, and IV—are present on both pre- and postF, whereas antigenic site Ø exists exclusively on preF. Additional preF-specific epitopes have been defined by antibodies MPE8 (17) and AM14 (21). Although serum mapping studies have shown that site Ø-directed antibodies are responsible for a large proportion of the neutralizing antibody response in most individuals (8), there are additional antibody specificities that contribute to serum neutralizing activity that remain to be defined. In addition, it was heretofore unknown whether certain antibody sequence features are required for recognition of certain neutralizing sites, as observed for other viral targets (22-25). Accordingly, understanding the relationship between neutralization potency and epitope specificity would be advantageous in the selection and/or design of vaccine antigens, as well as therapeutic and/or prophylactic antibodies, which induce potent neutralizing responses to RSV.

While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2^(nd) ed., Vol. 1, Raven Press, New York at pages 1045-1072).

Ribavirin, which is the only drug approved for treatment of infection, has been shown to be effective in the treatment of pneumonia and bronchiolitis associated with RSV infection, and has been shown to modify the course of severe RSV disease in immunocompetent children (Smith et ai., 1991, New Engl. J. Med. 325:24-29). The use of ribavirin is limited due to concerns surrounding its potential risk to pregnant women who may be exposed to the aerosolized drug while it is being administered in a hospital environment.

Similarly, while a vaccine may be useful, no commercially available vaccine has been developed to date. Several vaccine candidates have been abandoned and others are under development (Murphy et al., 1994, Virus Res. 32: 13-36). The development of a vaccine has proven to be problematic. In particular, immunization would be required in the immediate neonatal period since the peak incidence of lower respiratory tract disease occurs at 2-5 months of age. However, it is known that the neonatal immune response is immature at that time. Plus, the infant at that point in time still has high titers of maternally acquired RSV antibody, which might reduce vaccine immunogenicity (Murphy et al., 1988, J. Virol. 62:3907-3910; and Murphy et al, 1991, Vaccine 9:185-189).

Currently, the only approved approach to prophylaxis of RSV disease is passive immunization. For example, the humanized antibody, palivizumab (SYNAGIS®), which is specific for an epitope on the F protein, is approved for intramuscular administration to pediatric patients for prevention of serious lower respiratory tract disease caused by RSV at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is a composite of human (95%) and murine (5%) antibody sequences. (Johnson et al, (1997), J. Infect. Diseases 176:1215-1224 and U.S. Pat. No. 5,824,307).

Although SYNAGIS® has been successfully used for the prevention of RSV infection in pediatric patients, multiple intramuscular doses of 15 mg/kg of SYNAGIS® are required to achieve a prophylactic effect. The necessity for the administration of multiple intramuscular doses of antibody requires repeated visits to the doctor's office, which is not only inconvenient for the patient but can also result in missed doses.

Efforts were made to improve on the therapeutic profile of an anti-RSV-F antibody, and this lead to the identification and development of motavizumab, also referred to as NUMAX™. However, clinical testing revealed that certain of the patients being administered motavizumab were having severe hypersensitivity reactions. Further development of this humanized anti-RSV-F antibody was then discontinued.

Other antibodies to RSV-F protein have been described and can be found in U.S. Pat. No. 6,656,467; 5,824,307, 7,786,273; 7,670,600; 7,083,784; 6,818,216; 7,700,735; 7,553,489; 7,323,172; 7,229,619; 7,425,618; 7,740,851; 7,658,921; 7,704,505; 7,635,568; 6,855,493; 6,565,849; 7,582,297; 7,208,162; 7,700,720; 6,413,771; 5,811,524; 6,537,809; 5,762,905; 7,070,786; 7,364,742; 7,879,329; 7,488,477; 7,867,497; 5,534,411; 6,835,372; 7,482,024; 7,691,603; 8,562,996; 8,568,726; 9,447,173; U.S. 20100015596; WO2009088159A1; and WO2014159822. To date, none other than SYNAGIS® has been approved by a regulatory agency for use in preventing an RSV infection.

There remains a need for the provision of highly specific, high affinity, and highly potent neutralizing anti-RSV antibodies and antigen-binding fragments thereof with neutralize at least one, but preferably both, of subtype A and subtype B RSV viral strains, and which preferentially recognize PreF relative to PostF conformations of the F protein. There also remains a need for the provision of anti-RSV and anti-HMPV cross-neutralizing antibodies and antigen-binding fragments thereof.

SUMMARY OF THE INVENTION

Applicant has now discovered, isolated, and characterized, inter alia, an extensive panel of RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult human donor and used these antibodies to comprehensively map the antigenic topology of RSV F. A large proportion of the RSV F-specific human antibody repertoire was advantageously comprised of antibodies with greatly enhanced specificity for the PreF conformation of the F protein (relative to the PostF form), many if not most of which exhibited remarkable potency in neutralization assays against one or both of RSV subtype A and RSV subtype B strains. Indeed, a large number of these antibodies display neutralization potencies that are multiple-fold greater—some 5- to 100-fold greater or more—to previous anti-RSV therapeutic antibodies, such as D25 and pavlizumamab thus serve as attractive therapeutic and/or prophylactic candidates for treating and/or preventing RSV infection and disease.

The most potent antibodies were found to target two distinct antigenic sites that are located near the apex of the preF trimer, providing strong support for the development of therapeutic and/or prophylactic antibodies targeting these antigenic sites, as well as preF-based vaccine candidates that preserve these antigenic sites. Furthermore, the neutralizing antibodies described and disclosed herein represent new opportunities for the prevention of severe RSV disease using passive immunoprophylaxis.

Given the role that the F protein plays in fusion of the virus with the cell and in cell to cell transmission of the virus, the antibodies and pharmaceutical compositions described herein provide a method of inhibiting that process and as such, may be used for preventing infection of a patient exposed to, or at risk for acquiring an infection with RSV, or for treating and/or ameliorating one or more symptoms associated with RSV infection in a patient exposed to, or at risk for acquiring an infection with RSV, or suffering from infection with RSV. The antibodies described herein may also be used to prevent or to treat an RSV infection in a patient who may experience a more severe form of the RSV infection due to an underlying or pre-existing medical condition. A patient who may benefit from treatment with an antibody and/or a pharmaceutical composition of the invention may be a pre-term infant, a full-term infant born during RSV season (approximately late fall (November) through early spring (April)) that is at risk because of other pre-existing or underlying medical conditions including congenital heart disease or chronic lung disease, a child greater than one year of age with or without an underlying medical condition, an institutionalized or hospitalized patient, or an elderly adult (>65 years of age) with or without an underlying medical condition, such as congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD). A patient who may benefit from such therapy may suffer from a medical condition resulting from a compromised pulmonary, cardiovascular, neuromuscular, or immune system. For example, the patient may suffer from an abnormality of the airway, or an airway malfunction, a chronic lung disease, a chronic or congenital heart disease, a neuromuscular disease that compromises the handling of respiratory secretions, or the patient may be immunosuppressed due to severe combined immunodeficiency disease or severe acquired immunodeficiency disease, or from any other underlying infectious disease or cancerous condition that results in immunosuppression, or the patient may be immunosuppressed due to treatment with an immunosuppressive drug (e.g. any drug used for treating a transplant patient) or radiation therapy. A patient who may benefit from the antibodies and/or pharmaceutical compositions of the invention may be a patient that suffers from chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), bronchopulmonary dysplasia, congestive heart failure (CHF), or congenital heart disease.

Because the inventive antibodies and antigen-binding fragments thereof are more effective at neutralization of RSV compared to known antibodies, lower doses of the antibodies or antibody fragments or pharmaceutical composition of the invention could be used to achieve a greater level of protection against infection with RSV, and more effective treatment and/or amelioration of symptoms associated with an RSV infection. Accordingly, the use of lower doses of antibodies or fragments thereof which immunospecifically bind to RSV-F antigen may result in fewer or less severe adverse events. Likewise, the use of more effective neutralizing antibodies may result in a diminished need for frequent administration of the antibodies or antibody fragments or pharmaceutical compositions than previously envisioned as necessary for the prevention of infection, or for virus neutralization, or for treatment or amelioration of one or more symptoms associated with an RSV infection. Symptoms of RSV infection may include a bluish skin color due to lack of oxygen (hypoxia), breathing difficulty (rapid breathing or shortness of breath), cough, croupy cough (“seal bark” cough), fever, nasal flaring, nasal congestion (stuffy nose), apnea, decreased appetite, dehydration, poor feeding, altered mental status, or wheezing.

Such antibodies or pharmaceutical compositions may be useful when administered prophylactically (prior to exposure to the virus and infection with the virus) to lessen the severity, or duration of a primary infection with RSV, or ameliorate at least one symptom associated with the infection. The antibodies or pharmaceutical compositions may be used alone or in conjunction with a second agent useful for treating an RSV infection. In certain embodiments, the antibodies or pharmaceutical compositions may be given therapeutically (after exposure to and infection with the virus) either alone, or in conjunction with a second agent to lessen the severity or duration of the primary infection, or to ameliorate at least one symptom associated with the infection. In certain embodiments, the antibodies or pharmaceutical compositions may be used prophylactically as stand-alone therapy to protect patients who are at risk for acquiring an infection with RSV, such as those described above. Any of these patient populations may benefit from treatment with the antibodies of the invention, when given alone or in conjunction with a second agent, including for example, an anti-viral therapy, such as ribavirin, or other anti-viral vaccines.

The antibodies of the invention can be full-length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab′)₂ or scFv fragment), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al., (2000), J. Immunol. 164:1925-1933).

Accordingly, in certain embodiments are provided isolated antibodies or antigen-binding fragments thereof that specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one, at least two, at least three, at least four, at least five, or at least six of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence such antibodies or the antigen-binding fragments thereof are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one, at least two, at least three, at least four, at least five, or at least six the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics: a) the antibodies or antigen-binding fragments thereof cross-compete with said antibodies or antigen-binding fragments thereof for binding to RSV-F; b) the antibodies or antigen-binding fragments thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form; c) the antibodies or antigen-binding fragments thereof display a clean or low polyreactivity profile; d) the antibodies or antigen-binding fragments thereof display neutralization activity toward RSV subtype A and RSV subtype B in vitro; e) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F at Site Ø, Site I, Site II, Site III, Site IV, or Site V f) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the antibodies or antigen-binding fragments thereof interact comprises the α3 helix and β3/β4 hairpin of PreF; h) the antibodies or antigen-binding fragments thereof display an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (μg/ml) to about 5 μg/ml; between about 0.05 μg/ml to about 0.5 μg/ml; or less than about 0.05 mg/ml; i) the binding affinities and/or epitopic specificities of the antibodies or antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinities and/or epitopic specificities of said antibodies or antigen-binding fragments thereof for the RSV-F or RSV-F DS-Cav1; j) the antibodies or antigen-binding fragments thereof display a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV); k) the antibodies or antigen-binding fragments thereof do not complete with D25, MPEG, palivizumab, or motavizumab; or 1) the antibodies or antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through 1) above.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; or g) any combination of two or more of a), b), c), d), e), and f).

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; and/or b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In other embodiments are provided isolated nucleic acid sequences encoding antibodies, or antigen-binding fragments thereof, or light and/or heavy chains thereof according to any of the other embodiments disclosed herein.

In other embodiments are provided expression vectors comprising isolated nucleic acid sequences according to other embodiments disclosed herein.

In other embodiments are provided host cells transfected, transformed, or transduced with nucleic acid sequences or expression vectors according to other embodiments disclosed herein.

In other embodiments are provided pharmaceutical compositions comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.

In other embodiments are provided pharmaceutical compositions: one or more nucleic acid sequences according other embodiments disclosed herein; or one or more the expression vectors according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.

In other embodiments are provided transgenic organisms comprising nucleic acid sequences according to other embodiments disclosed herein; or expression vectors according to other embodiments disclosed herein.

In other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need there of or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) nucleic acid sequences according to other embodiments disclosed herein; an expression vector according to other embodiments disclosed herein; a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) a nucleic acid sequences according to other embodiments disclosed herein; c) an expression vector according to other embodiments disclosed herein; d)a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In other embodiments are provided methods according to other embodiments wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies desifgnated as Antibody Number 179, 188, 211, 221, or 229 as disclosed in Table 6.

In other embodiments are provided methods according to other embodiments wherein the method further comprises administering to the patient a second therapeutic agent.

In other embodiments are provided methods according to other embodiments, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.

In certain embodiments are provided pharmaceutical compositions comprising any one or more of the isolated antibodies or antigen-binding fragments thereof and a pharmaceutically acceptable carrier and/or excipient.

In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in treating or preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.

In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection and/or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection and/or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1F illustrate the anti-RSV repertoire cloning and sequence analysis of the identified and isolated antibodies. FIG. 1A: RSV F-specific B cell sorting. FACS plots show RSV F reactivity of IgG⁺ and IgA⁺ B cells from the healthy adult human donor. B cells in quadrant 2 (Q2) were single cell sorted. FIG. 1B: Isotype analysis. Index sort plots show the percentage of RSV F-specific B cells that express IgG or IgA. FIG. 1C: Clonal lineage analysis. Each slice represents one clonal lineage; the size of the slice is proportional to the number of clones in the lineage. The total number of clones is shown in the center of the pie. Clonal lineages were assigned based on the following criteria: 1) matching of variable and joining gene segments; 2) identical CDR3 loop lengths; and 3) >80% homology in CDR3 nucleotide sequences. FIG. 1D: VH repertoire analysis. VH germline genes were considered to be enriched in the RSV repertoire if a given gene was found to be enriched by greater than 3-fold over non-RSV-specific repertoires (33). FIG. 1E: CDRH3 length distribution. FIG. 1F: Somatic hypermutation in VH (excluding CDRH3). Red bar indicates the average number of nucleotide substitutions. Each clonal lineage is only represented once in FIG. 1D and FIG. 1E. Data for non-RSV reactive IgGs were derived from published sequences obtained by high-throughput sequencing of re-arranged antibody variable gene repertoires from healthy individuals (33).

FIGS. 2A-2D illustrate the similar antibody preferences observed for conformational state and subtype of RSV F in the repertoire. FIG. 2A: IgG affinities for preF and postF are plotted as shown. FIG. 2B: Percentage of antibodies within the donor repertoire that recognized both conformations of F (green) or bind only to preF (blue) or postF (orange). FIG. 2C: Percentage of antibodies within the donor repertoire that bind specifically to subtype A (green), subtype B (blue), or both subtypes A and B (red). N.B., non-binder. IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. FIG. 2D: Polyreactivity analysis of anti-RSV antibodies. The polyreactivity of the isolated anti-RSV F antibodies was measured using a previously described assay (42, 43). Three panels of control antibodies were included for comparison: a group of 138 antibodies currently in clinical trials, 39 antibodies that have been approved for clinical use and 14 broadly neutralizing HIV antibodies.

FIGS. 3A-3G illustrate mapping and specificities of anti-RSV antibodies for antigenic sites spanning the surface of PreF and PostF. FIG. 3A: The previously determined structure of preF with one protomer shown as ribbons and with six antigenic sites rainbow colored from red to purple. FIG. 3B: The percentage of antibodies targeting each antigenic site is shown. FIG. 3C: Percentage of preF-specific antibodies targeting each antigenic site. FIG. 3D: Apparent antibody binding affinities for subtype A PreF antigenic sites. FIG. 3E: Apparent binding affinities for subtype A postF antigenic sites. FIG. 3F: Apparent antibody binding affinities for subtype B PreF antigenic sites. FIG. 3G. Apparent binding affinities for subtype B postF. Only antibodies with apparent binding affinities greater than 2 nM were included in this analysis, since antibodies with lower affinity could not be reliably mapped. Red bars show the median and the dotted grey line is at 2 nM. N.B., non-binder.

FIGS. 4A-4G illustrate neutralizing potencies of anti-RSV antibodies and correlation between potency and Pref vs. PostF specificity for each of RSV subtypes A and B. FIG. 4A: Neutralization IC₅₀s for the antibodies isolated from the donor repertoire. Data points are colored based on neutralization potency, according to the legend on the right. Red and blue dotted lines depict motavizumab and D25 IC₅₀s, respectively. FIG. 4B: Percentage of neutralizing antibodies in the donor repertoire against RSV subtype A or subtype B, stratified by potency as indicated in the legend in the right portion of the figure. FIG. 4C: Percentage of antibodies within the donor repertoire that neutralized both RSV subtypes A and B (red) or neutralized only RSV subtype A (green) or subtype B (blue). FIG. 4D: Apparent binding affinities for subtype A, preF and postF, plotted for each antibody (IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B.) FIG. 4E: Neutralization IC₅₀s plotted for RSV subtype A preF-specific, postF-specific, and cross-reactive antibodies. (Red and blue dotted lines depict motavizumab and D25 IC₅₀s, respectively. Red bars depict median. N.B., non-binder; N.N., non-neutralizing). FIG. 4F: Apparent antibody binding affinities for subtype B, preF and postF. FIG. 4G: IC₅₀s plotted for RSV subtype B preF-specific, postF-specific and cross-reactive antibodies. (Black bar depicts median. N.B., non-binder; N.N., non-neutralizing.)

FIGS. 5A-5C illustrate that the most potent neutralizing antibodies bind with high affinity to preF and recognize antigenic sites Ø and V. FIG. 5A: apparent preF K_(D) plotted against neutralization IC₅₀ and colored according to antigenic site, as shown in the legend at right of FIG. 5C. FIG. 5B: apparent postF K_(D) plotted against neutralization IC₅₀ and colored as in FIG. 5A. FIG. 5C: antibodies grouped according to neutralization potency and colored by antigenic site as in legend at right. N.B., non-binder; N.N., non-neutralizing. IgG K_(D)s were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. Statistical significance was determined using an unpaired two-tailed t test. The Pearson's correlation coefficient, r, was calculated using Prism software version 7.0. Antibodies that failed to bind or neutralize were excluded from the statistical analysis due to the inability to accurately calculate midpoint concentrations.

FIGS. 6A-6C illustrate the nature and purification of pre- and postF sorting probes. FIG. 6A: Schematic of fluorescent prefusion RSV F probe shows one PE-conjugated streptavidin molecule bound by four avi-tagged trimeric prefusion F molecules. FIG. 6B: Coomassie-stained SDS-PAGE gel demonstrating the isolation of RSV F with a single AviTag per trimer using sequential Ni-NTA and Strep-Tactin purifications, as described in the Methods. FIG. 6C: Fluorescence size-exclusion chromatography (FSEC) trace of the tetrameric probes on a Superose 6 column. Positions of molecular weight standards are indicated with arrows.

FIGS. 7A-7C illustrate the generation and validation of preF patch panel mutants. FIG. 7A: Panel of RSV F variants used for epitope mapping. FIG. 7B: Prefusion RSV F shown as molecular surface with one protomer colored in white. The nine variants, each containing a patch of mutations, are uniquely colored according to the table in FIG. 7A. FIG. 7C: Binding of each IgG to fluorescently labeled beads coupled to each of the variants listed in FIG. 7A was measured using PE-conjugated anti-human Fc antibody on a FLEXMAP 3D flow cytometer (Luminex). Reduced binding of D25 and motavizumab to patches 1 and 5, respectively, is consistent with their structurally defined epitopes (10, 11). AM14 binding was reduced for both patch 3 and patch 9, due to its unique protomer-spanning epitope (21). This characteristic binding profile was used to assist in the classification of other possible quaternary-specific antibodies in the panel.

FIG. 8 illustrates the antigenic site V resides between the epitopes recognized by D25, MPE8 and motavizumab. Prefusion F is shown with one promoter as a cartoon colored according to antigenic site location and the other two protomers colored grey. D25 and motavizumab Fabs are shown in blue and pink, respectively. The MPE8 binding site is circled in black. Antigenic site V is located between the binding sites of D25 and MPE8 within one protomer, explaining the competition between site-V directed antibodies and these controls. Competition with motavizumab may occur across two adjacent protomers (left) or within one protomer (right), depending on the angle-of-approach of these site-V directed antibodies.

FIG. 9 illustrates percentage of anti-RSV antibodies demonstrating the indicated neutralizing activities of preF-specific, postF-specific, and cross-reactive antibodies. Antibodies were stratified according to neutralization potency and the percentage of antibodies in each group that were preF-specific (pink), postF-specific (white) or cross-reactive (orange) were plotted for subtype A (left panel) and subtype B (right panel).

FIGS. 10A-10C illustrate the relationship between subtype B neutralization and antigenic site specificity for anti-RSV antibodies. FIG. 10A: Subtype B preF affinity plotted against neutralization IC₅₀ for all antibodies and colored by antigenic site according to the colore scheme depicted in FIG. 10C, right portion. FIG. 10B: PostF affinity plotted against IC₅₀ and colored as in FIG. 10A. FIG. 10C: Antibodies with preF affinities higher than 2 nM grouped according to neutralization potency and colored by antigenic site (right portion).

FIG. 11 illustrates in vitro neutralization of RSV A2. Inhibition of RSV-replication was measured in an ELISA based neutralization Assay using Hep-2 cells. Cells, mAbs and viruses were co-incubated for 4 days at 37° C., followed by quantification of viral proteins in infected cells using a polyclonal anti-RSV antibody. % inhibition was calculated relative to control cells infected with virus in absence of neutralizing antibody. Data are expressed as half-maximal inhibitory concentration that resulted in 50% reduction in virus replication (IC50) and represent the mean +/−SEM of two independent experiments. An isotype matched control mAb (*) was included in every experiment and did not exhibit virus neutralization.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term “about,” when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

Definitions

“Respiratory Syncytial Virus-F protein”, also referred to as “RSV-F” or “RSV F” is a type I transmembrane surface protein, which has an N terminal cleaved signal peptide and a membrane anchor near the C terminus (Collins, P. L. et al., (1984), PNAS (USA) 81 :7683-7687). The RSV-F protein is synthesized as an inactive 67 KDa precursor denoted as F0 (Calder, L. J.; et al., Virology (2000), 277,122-131. The F0 protein is activated proteolytically in the Golgi complex by a furin-like protease at two sites, yielding two disulfide linked polypeptides, F2 and F1, from the N and C terminal, respectively. There is a 27 amino acid peptide released called “pep27”. There are furin cleavage sites (FCS) on either side of the pep27 (Collins, P. L.; Mottet, G. (1991), J. Gen. Virol., 72: 3095-3101 ; Sugrue, R. J., et al. (2001), J. Gen. Virol., 82, 1375-1386). The F2 subunit consists of the Heptad repeat C (HRC), while the F1 contains the fusion polypeptide (FP), heptad repeat A (HRA), domain I, domain II, heptad repeat B (HRB), transmembrane (™) and cytoplasmic domain (CP) (See Sun, Z. et al. Viruses (2013), 5:21 1-225). The RSV-F protein plays a role in fusion of the virus particle to the cell membrane, and is expressed on the surface of infected cells, thus playing a role in cell to cell transmission of the virus and syncytia formation. The amino acid sequence of the RSV-F protein is provided in GenBank as accession number AAX23994.

A stabilized variant of the PreF trimeric conformation of RSV-F, termed “RSV-DS-Cav1”, or “DS-Cav1” disclosed in, inter alia, Stewart-Jones et al., PLos One, Vol. 10(6) e0128779 and WO 2011/050168 was used in the identification, isolation, and characterization of the antibodies disclosed herein.

The term “laboratory strain” as used herein refers to a strain of RSV (subtype A or B) that has been passaged extensively in in vitro cell culture. A “laboratory strain” can acquire adaptive mutations that may affect their biological properties. A “clinical strain” as used herein refers to an RSV isolate (subtype A or B), which is obtained from an infected individual and which has been isolated and grown in tissue culture at low passage.

The term “effective dose 99” or “ED₉₉” refers to the dosage of an agent that produces a desired effect of 99% reduction of viral forming plaques relative to the isotype (negative) control. In the present invention, the ED₉₉ refers to the dosage of the anti-RSV-F antibodies that will neutralize the virus infection (i.e., reduce 99% of viral load) in vivo, as described in Example 5.

The term “IC₅₀” refers to the “half maximal inhibitory concentration”, which value measures the effectiveness of compound (e.g. anti-RSV-F antibody) inhibition towards a biological or biochemical utility. This quantitative measure indicates the quantity required for a particular inhibitor to inhibit a given biological process by half In certain embodiments, RSV virus neutralization potencies for anti-RSV and/or anti-RSV/anti-HMPV cross-neutralizing antibodies disclosed herein are expressed as neutralization IC₅₀ values.

“Palivizumab”, also referred to as “SYNAGIS®”, is a humanized anti-RSV-F antibody with heavy and light chain variable domains having the amino acid sequences as set forth in U.S. Pat. No. 7,635,568 and U.S. Pat. No. 5,824,307. This antibody, which immunospecifically binds to the RSV-F protein, is currently FDA-approved for the passive immunoprophylaxis of serious RSV disease in high-risk children and is administered intramuscularly at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is composed of 95% human and 5% murine antibody sequences. See also Johnson et al., (1997), J. Infect. Diseases 176:1215-1224.

“Motavizumab”, also referred to as “NUMAX™”, is an enhanced potency RSV-F-specific humanized monoclonal antibody derived by in vitro affinity maturation of the complementarity-determining regions of the heavy and light chains of palivizumab. For reference purposes, the amino acid sequence of the NUMAX™ antibody is disclosed in U.S. Patent Publication 2003/0091584 and in U.S. Pat. No. 6,818,216 and in Wu et al., (2005) J. Mol. Bio. 350(1):126-144 and in Wu, et al. (2007) J. Mol. Biol. 368:652-665. It is also shown herein as SEQ ID NO: 359 for the heavy chain and as SEQ ID NO: 360 for the light chain of the antibody.

As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of an upper and/or lower respiratory tract RSV infection and/or human metapneumovirus (HMPV), otitis media, or a symptom or respiratory condition related thereto (such as asthma, wheezing, or a combination thereof) resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents). In certain embodiments, such terms refer to the reduction or inhibition of the replication of RSV and/or HMPV, the inhibition or reduction in the spread of RSV and/or HMPV to other tissues or subjects (e.g., the spread to the lower respiratory tract), the inhibition or reduction of infection of a cell with a RSV and/or HMPV, or the amelioration of one or more symptoms associated with an upper and/or lower respiratory tract RSV infection or otitis media.

As used herein, the terms “prevent,” “preventing,” and “prevention” refer to the prevention or inhibition of the development or onset of an upper and/or lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto in a subject, the prevention or inhibition of the progression of an upper respiratory tract RSV and/or HMPV infection to a lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto resulting from the administration of a therapy (e.g., a prophylactic or therapeutic agent), the prevention of a symptom of an upper and/or lower tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto, or the administration of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents). As used herein, the terms “ameliorate” and “alleviate” refer to a reduction or diminishment in the severity a condition or any symptoms thereof.

The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds (i.e., “full antibody molecules”), as well as multimers thereof (e.g. IgM) or antigen-binding fragments thereof. Each heavy chain (HC) is comprised of a heavy chain variable region (“HCVR” or “V_(H)”) and a heavy chain constant region (comprised of domains C_(H)1 , C_(H)2 and C_(H)3). Each light chain (LC) is comprised of a light chain variable region (“LCVR or “V_(L)”) and a light chain constant region (CO. The V_(H) and V_(L) regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each V_(H) and V_(L) is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1 , FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the invention, the FRs of the antibody (or antigen binding fragment thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs. Accordingly, the CDRs in a heavy chain are designated “CHRH1”, “CDRH2”, and “CDRH3”, respectively, and the CDRs in a light chain are designated “CDRL1”, “CDRL2”, and “CDRL3”.

Substitution of one or more CDR residues or omission of one or more CDRs is also possible. Antibodies have been described in the scientific literature in which one or two CDRs can be dispensed with for binding. Padlan et al. (1995 FASEB J. 9:133-139) analyzed the contact regions between antibodies and their antigens, based on published crystal structures, and concluded that only about one fifth to one third of CDR residues actually contact the antigen. Padlan also found many antibodies in which one or two CDRs had no amino acids in contact with an antigen (see also, Vaj dos et al. 2002 J Mol Biol 320:415-428).

CDR residues not contacting antigen can be identified based on previous studies (for example residues H60-H65 in CDRH2 are often not required), from regions of Kabat CDRs lying outside Chothia CDRs, by molecular modeling and/or empirically. If a CDR or residue(s) thereof is omitted, it is usually substituted with an amino acid occupying the corresponding position in another human antibody sequence or a consensus of such sequences. Positions for substitution within CDRs and amino acids to substitute can also be selected empirically.

The fully human monoclonal antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof In certain embodiments, all of the framework and/or CDR residues within the V_(H) and/or V_(L) domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

The present invention also includes fully monoclonal antibodies comprising variants of any of the CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes antibodies having CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the CDR amino acid sequences disclosed herein.

The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human mAbs of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.

However, the term “human antibody”, as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., mouse), have been grafted onto human FR sequences.

The term “humanized antibody” refers to human antibody in which one or more CDRs of such antibody have been replaced with one or more corresponding CDRs obtained a non-human derived (e.g., mouse, rat, rabbit, primate) antibody. Humanized antibodies may also include certain non-CDR sequences or residues derived from such non-human antibodies as well as the one or more non-human CDR sequence. Such antibodies may also be referred to as “chimeric” antibodies.

The term “recombinant” generally refers to any protein, polypeptide, or cell expressing a gene of interest that is produced by genetic engineering methods. The term “recombinant” as used with respect to a protein or polypeptide, means a polypeptide produced by expression of a recombinant polynucleotide. The proteins used in the immunogenic compositions of the invention may be isolated from a natural source or produced by genetic engineering methods.

The antibodies of the invention may, in some embodiments, be recombinant human antibodies. The term “recombinant human antibody”, as used herein, is intended to include all antibodies, including human or humanized antibodies, that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V_(H) and V_(L) regions of the recombinant antibodies are sequences that, while derived from and related to human germline V_(H) and V_(L) sequences, may not naturally exist within the human antibody germline repertoire in vivo.

The term “specifically binds,” or “binds specifically to”, or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about 1×10⁻⁶ M or less (e.g., a smaller K_(D) denotes a tighter binding). Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. As described herein, antibodies have been identified by surface plasmon resonance, e.g., BIACORE™, biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), which bind specifically to RSV-F. Moreover, multi-specific antibodies that bind to RSV-F protein and one or more additional antigens, such as an antigen expressed by HMPV, or a bi-specific that binds to two different regions of RSV-F are nonetheless considered antibodies that “specifically bind”, as used herein. In certain embodiments, the antibodies disclosed herein display equilibrium dissociation constants (and hence specificities) of about 1×10−⁶M; about 1×10−⁷ M; about 1×10−⁸M; about 1×10−⁹ M; about 1×10⁻¹⁰ M; between about 1×10⁻⁶M and about 1×10−⁷ M; between about 1×10−⁷M and about 1×10−⁸ M; between about 1×10−⁸ M and about 1×10−⁹ M; or between about 1×10−⁹ M and about 1×10−¹⁰ M.

The term “high affinity” antibody refers to those mAbs having a binding affinity to RSV-F and/or HMPV, expressed as K_(D), of at least 10−⁹M; more preferably 10−¹⁰M, more preferably 10⁻¹¹M, more preferably 10⁻¹²M as measured by surface plasmon resonance, e.g., BIACORE™, biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), or solution-affinity ELISA.

By the term “slow off rate”, “Koff” or “kd” is meant an antibody that dissociates from RSV-F, with a rate constant of 1×10⁻³ s^(″1) or less, preferably 1×10⁻⁴ s^(″1) or less, as determined by surface plasmon resonance, e.g., BIACORE™ or a ForteBio Octet HTX instrument (Pall Life Sciences).

The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. In certain embodiments, the terms “antigen-binding portion” of an antibody, or “antibody fragment”, as used herein, refers to one or more fragments of an antibody that retains the ability to bind to RSV-F and/or HMPV.

An antibody fragment may include a Fab fragment, a F(ab′)₂fragment, a Fv fragment, a dAb fragment, a fragment containing a CDR, or an isolated CDR. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and (optionally) constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab′)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment,” as used herein.

An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR, which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a V_(H) domain associated with a V_(L) domain, the V_(H) and V|_ domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain V_(H)-V_(H), V_(H)-V_(L) or V_(L)-V_(L) dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric V_(H) or V_(L) domain.

In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) V_(H)-C_(H)1; (ii) V_(H)-C_(H)2; (iii) V_(H)-C_(H)3; (iv) V_(H)-C_(h)1-C_(h)2; (v) V_(H)-C_(h)1-C_(h)2-C_(h)3; (vi) V_(H)-C_(H)2-C_(H)3; (vii) V_(H)-C_(L); V_(L)-C_(H)1 ; (ix) V_(L)-C_(H)2; (x) V_(L)-C_(H)3; (xi) V_(L)-C_(H)1-C_(H)2; (xii) V_(L)-C_(H)1-C_(H)2-C_(H)3; (xiii) V_(L)-C_(H)2-C_(H)3; and (xiv) V_(L)-C_(L). In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V_(H) or V_(L) domain (e.g., by disulfide bond(s)).

As with full antibody molecules, antigen-binding fragments may be mono-specific or multi-specific (e.g., bi-specific). A multi-specific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multi-specific antibody format, including the exemplary bi-specific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.

The specific embodiments, antibody or antibody fragments of the invention may be conjugated to a therapeutic moiety (“immunoconjugate”), such as an antibiotic, a second anti-RSV-F antibody, an anti-HMPV antibody, a vaccine, or a toxoid, or any other therapeutic moiety useful for treating an RSV infection and/or an HMPV infection.

An “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies (Abs) having different antigenic specificities (e.g., an isolated antibody that specifically binds RSV-F and/or HMPV, or a fragment thereof, is substantially free of Abs that specifically bind antigens other than RSV-F and/or HMPV.

A “blocking antibody” or a “neutralizing antibody”, as used herein (or an “antibody that neutralizes RSV-F and/or HMPV activity”), is intended to refer to an antibody whose binding to RSV-F or to an HMPV antigen, as the case may be as disclosed herein, results in inhibition of at least one biological activity of RSV-F and/or HMPV. For example, an antibody of the invention may aid in blocking the fusion of RSV and/or HMPV to a host cell, or prevent syncytia formation, or prevent the primary disease caused by RSV and/or HMPV. Alternatively, an antibody of the invention may demonstrate the ability to ameliorate at least one symptom of the RSV infection and or HMPV infection. This inhibition of the biological activity of RSV-F and/or HMPV can be assessed by measuring one or more indicators of RSV-F and/or HMPV biological activity by one or more of several standard in vitro assays (such as a neutralization assay, as described herein) or in vivo assays known in the art (for example, animal models to look at protection from challenge with RSV and/or HMPV following administration of one or more of the antibodies described herein).

The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time biomolecular interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE™ system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).

The term “K_(D)”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. The term “epitope” also refers to a site on an antigen to which B and/or T cells respond. It also refers to a region of an antigen that is bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, that is, composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics.

The term “substantial identity”, or “substantially identical,” when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, and more preferably at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or GAP, as discussed below. Accordingly, nucleic acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

In certain embodiments, the disclosed antibody nucleic acid sequences are, e..g,: at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

As applied to polypeptides, the term “substantial identity” or “substantially identical” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 90% sequence identity, even more preferably at least 95%, 98% or 99% sequence identity. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another.

In certain embodiments, the disclosed antibody amino acid sequences are, e.g.,: at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).

Preferably, residue positions, which are not identical, differ by conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art. (See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331). Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate, and 7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as GAP and BESTFIT which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA with default or recommended parameters; a program in GCG Version 6.1. FASTA {e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. (See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and (1997) Nucleic Acids Res. 25:3389 402).

In certain embodiments, the antibody or antibody fragment for use in the method of the invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first and second Ig C_(H)3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig C_(H)3 domain binds Protein A and the second Ig C_(H)3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second C_(H)3 may further comprise an Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second C_(H)3 include: D16E, L18M, N44S, K52N, V57M, and V821 (by IMGT; D356E, L358M, N384S, K392N, V397M, and V4221 by EU) in the case of IgG1 mAbs; N44S, K52N, and V821 (IMGT; N384S, K392N, and V4221 by EU) in the case of IgG2 mAbs; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V821 (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V4221 by EU) in the case of IgG4 mAbs. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.

By the phrase “therapeutically effective amount” is meant an amount that produces the desired effect for which it is administered. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

An “immunogenic composition” relates to a composition containing an antigen/immunogen, e.g. a microorganism, such as a virus or a bacterium, or a component thereof, a protein, a polypeptide, a fragment of a protein or polypeptide, a whole cell inactivated, subunit or attenuated virus, or a polysaccharide, or combination thereof, administered to stimulate the recipient's humoral and/or cellular immune systems to one or more of the antigens/immunogens present in the immunogenic composition. The immunogenic compositions of the present invention can be used to treat a human susceptible to RSV and/or HMPV infection or suspected of having or being susceptible to RSV and/or HMPV infection, by means of administering the immunogenic compositions via a systemic route. These administrations can include injection via the intramuscular (i.m.), intradermal (i.d.), intranasal or inhalation route, or subcutaneous (s.c.) routes; application by a patch or other transdermal delivery device. In one embodiment, the immunogenic composition may be used in the manufacture of a vaccine or in the elicitation of polyclonal or monoclonal antibodies that could be used to passively protect or treat a mammal.

The terms “vaccine” or “vaccine composition”, which are used interchangeably, refer to a composition comprising at least one immunogenic composition that induces an immune response in an animal.

In certain embodiments, a protein of interest comprises an antigen. The terms “antigen,” “immunogen,” “antigenic,” “immunogenic,” “antigenically active,” and “immunologically active” when made in reference to a molecule, refer to any substance that is capable of inducing a specific humoral and/or cell-mediated immune response. In one embodiment, the antigen comprises an epitope, as defined above.

“Immunologically protective amount”, as used herein, is an amount of an antigen effective to induce an immunogenic response in the recipient that is adequate to prevent or ameliorate signs or symptoms of disease, including adverse health effects or complications thereof. Either humoral immunity or cell-mediated immunity or both can be induced. The immunogenic response of an animal to a composition can be evaluated, e.g., indirectly through measurement of antibody titers, lymphocyte proliferation assays, or directly through monitoring signs and symptoms after challenge with the microorganism. The protective immunity conferred by an immunogenic composition or vaccine can be evaluated by measuring, e.g., reduction of shed of challenge organisms, reduction in clinical signs such as mortality, morbidity, temperature, and overall physical condition, health and performance of the subject. The immune response can comprise, without limitation, induction of cellular and/or humoral immunity. The amount of a composition or vaccine that is therapeutically effective can vary, depending on the particular organism used, or the condition of the animal being treated or vaccinated.

An “immune response”, or “immunological response” as used herein, in a subject refers to the development of a humoral immune response, a cellular-immune response, or a humoral and a cellular immune response to an antigen/immunogen. A “humoral immune response” refers to one that is at least in part mediated by antibodies. A “cellular immune response” is one mediated by T-lymphocytes or other white blood cells or both, and includes the production of cytokines, chemokines and similar molecules produced by activated T-cells, white blood cells, or both. Immune responses can be determined using standard immunoassays and neutralization assays, which are known in the art.

“Immunogenicity”, as used herein, refers to the capability of a protein or polypeptide to elicit an immune response directed specifically against a bacteria or virus that causes the identified disease.

Unless specifically indicated otherwise, the term “antibody,” as used herein, shall be understood to encompass antibody molecules comprising two immunoglobulin heavy chains and two immunoglobulin light chains (i.e., “full antibody molecules”) as well as antigen-binding fragments thereof. The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.

Preparation of Human Antibodies

As disclosed herein, anti-RSV and or anti-RSV/anti-HMPF cross neutralizing antibodies by be obtained through B cell sorting techniques available to the artisan, and, for example, as described in the EXAMPLES below. Methods for generating human antibodies in transgenic mice are also known in the art and may be employed in order to derive antibodies in accordance with the present disclosure. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to RSV-F (see, for example, U.S. Pat. No. 6,596,541).

In certain embodiments, the antibodies of the instant invention possess affinities (K_(D)) ranging from about 1.0×10−⁷M to about 1.0×10⁻¹²M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (K_(D)) ranging from about 1×10⁻⁷ M to about 6×10⁻¹⁰M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (K_(D)) ranging from about 1×10⁻⁷ M to about 9×10⁻¹⁰ M, when measured by binding to antigen either immobilized on solid phase or in solution phase.

The anti-RSV-F and/or anti-HMPV antibodies and antibody fragments disclosed herein encompass proteins having amino acid sequences that vary from those of the described antibodies, but that retain the ability to bind RSV-F. Such variant antibodies and antibody fragments comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies. Likewise, the antibody-encoding DNA sequences of the present invention encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an antibody or antibody fragment that is essentially bioequivalent to an antibody or antibody fragment of the invention.

Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single does or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.

In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

In one embodiment, two antigen-binding proteins are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.

In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.

Bioequivalence may be demonstrated by in vivo and/or in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.

Bioequivalent variants of the antibodies of the invention may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antibodies may include antibody variants comprising amino acid changes, which modify the glycosylation characteristics of the antibodies, e.g., mutations that eliminate or remove glycosylation.

Biological and Biophysical Characteristics of the Antibodies

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical, or 100% identical; and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such antibodies also possess at least one, two, three, four, five, six, seven, eight, nine, ten, or more characteristics disclosed in the immediately following eleven paragraphs.

Without wishing to be bound by any theory, it is believed that the inventive antibodies and antigen-binding fragments thereof may function by binding to RSV-F, preferably in the PreF conformation, and in so doing act to block the fusion of the viral membrane with the host cell membrane. The antibodies of the present invention may also function by binding to RSV-F and in so doing block the cell to cell spread of the virus and block syncytia formation associated with RSV infection of cells. Advantageously, both RSV subtype A and RSV subtype B are effectively blocked, or neutralized, by the majority of the anti-RSV antibodies disclosed herein.

In certain embodiments, the inventive antibodies and antigen-binding fragment thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form of RSV-F.

In certain other embodiments, the inventive antibodies and antigen-binding fragments thereof advantageously display a clean or low polyreactivity profile (see, e.g., WO 2014/179363 and Xu et al., Protein Eng Des Sel, Oct; 26(10):663-70), and are thus particularly amenable to development as safe, efficacious, and developable therapeutic and/or prophylactic anti-RSV and/or HMPV treatments.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof, without wishing to be bound by any theory, may function by blocking or inhibiting RSV fusion to the cell membrane by binding to any one or more of, e.g., antigenic Sites Ø, I, II, III, IV, or Site V of the PreF conformation of the F protein. In certain embodiments, the inventive antibodies display antigenic site specificity for Site Ø, Site V, or Site III of PreF relative to RSV-F Site I, Site II, or Site IV.

In certain embodiments, at least a portion of the epitope with which the inventive antibodies and antigen-binding fragments thereof interacts comprises a portion of the α3 helix and β3/β4 hairpin of PreF. In certain embodiments, substantially all of the epitope of such antibodies comprises the α3 helix and β3/β4 hairpin of PreF. In still further embodiments, the inventive antibodies cross-copmpete with antibodies that recognize a portion or substantially allof the α3 helix and β3/β4 hairpin of PreF.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (μg/ml) to about 5 μg/ml; between about 0.05 μg/ml to about 0.5 μg/ml; or less than about 0.05 mg/ml.

In certain embodiments, the binding affinity and/or epitopic specificity of the inventive antibodies and antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display a cross-neutralization potency (IC₅₀) against human metapneumovirus (HMPV) as well as RSV. In certain such embodiments, the inventive antibodies and antigen-binding fragments thereof comprise at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; or 100% identical; and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from the group consisting of Antibody Number 179, 188, 211, 221, and 229 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, motavizumab, or AM-14. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with palivisumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with motavizumab.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof complete with one or more of D25, MPEG, palivisumab, motavizumab, and/or AM-14.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise any combination of two, three, four, five, or six characteristics disclosed in the immediately preceeding six paragraphs.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence and a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof are each selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; 100% identical; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise are each selected from the group consisting of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

In certain embodiments, isolated nucleic acid sequences are provided that encode antibodies or antigen binding fragments thereof that specifically bind to Respiratory Syncytial Virus (RSV) F protein and antigen-binding fragments thereof, wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; 100% identical; and/or all percentages of identity in between; to at least one the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH3 amino acid sequence of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH2 amino acid sequences of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH1 amino acid sequences of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL3 amino acid sequences of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL2 amino acid sequences of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL1 amino acid sequences of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the heavy chain (HC) amino acid sequences of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the heavy chain (LC) amino acid sequences of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences are each selected from the group consisting of sequences that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99% identical; 100% identical; and/or all percentages of identity in between; to any one of the nucleic acid seuences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, expression vectors are provided comprising the isolated nucleic acid sequences disclose herein and throughout, and in particular in the immedivately preceeding ten paragraphs.

In certain embodiments, host cells transfected, transformed, or transduced with the nucleic acid sequences and/or the expression vectors disclosed immediately above are provided.

Epitope Mapping and Related Technologies

As described above and as demonstrated in the EXAMPLES, Applicant has characterized the epitopic specificities, bin assignments, and antigenic site assignments of the inventive antibodies and antigen-binding fragments thereof. In addition to the methods for conducting such characterization, various other techniques are available to the artisan that can be used to carry out such characterization or to otherwise ascertain whether an antibody “interacts with one or more amino acids” within a polypeptide or protein. Exemplary techniques include, for example, a routine cross-blocking assay such as that described Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., N.Y.) can be performed. Other methods include alanine scanning mutational analysis, peptide blot analysis (Reineke (2004) Methods Mol Biol 248:443-63), peptide cleavage analysis crystallographic studies and NMR analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen/deuterium exchange detected by mass spectrometry. In general terms, the hydrogen/deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium-labeled protein. Next, the protein/antibody complex is transferred to water and exchangeable protons within amino acids that are protected by the antibody complex undergo deuterium-to-hydrogen back-exchange at a slower rate than exchangeable protons within amino acids that are not part of the interface. As a result, amino acids that form part of the protein/antibody interface may retain deuterium and therefore exhibit relatively higher mass compared to amino acids not included in the interface. After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues that correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring (1999) Analytical Biochemistry 267 (2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

As the artisan will understand, an epitope can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.

Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (U.S. Publ. No. 2004/0101920). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma clones that produce mAbs having the desired characteristics. MAP may be used to sort the antibodies of the invention into groups of antibodies binding different epitopes.

In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in one or more of the F protein patch variants disclosed, e.g., in the EXAMPLES and which are depicted in, e.g., FIG. 7A and which are designated as RSV F Variants 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG. In certain embodiments, such inventive antibodies and antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in RSV F Variant 2. In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with amino acid residues that extend beyond the region(s) identified above by about 5 to 10 amino acid residues, or by about 10 to 15 amino acid residues, or by about 15 to 20 amino acid residues towards either the amino terminal or the carboxy terminal of the RSV-F protein.

In certain embodiments, the antibodies of the present invention do not bind to the same epitope on RSV-F protein as palivizumab, motavizumab, MPE8, or AM-14.

As the artisan understands, one can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-RSV-F antibody by using routine methods available in the art. For example, to determine if a test antibody binds to the same epitope as a reference RSV-F antibody of the invention, the reference antibody is allowed to bind to a RSV-F protein or peptide under saturating conditions. Next, the ability of a test antibody to bind to the RSV-F molecule is assessed. If the test antibody is able to bind to RSV-F following saturation binding with the reference anti-RSV-F antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-RSV-F antibody. On the other hand, if the test antibody is not able to bind to the RSV-F molecule following saturation binding with the reference anti-RSV-F antibody, then the test antibody may bind to the same epitope as the epitope bound by the reference anti-RSV-F antibody of the invention.

To determine if an antibody competes for binding with a reference anti-RSV-F antibody, the above-described binding methodology is performed in two orientations: In a first orientation, the reference antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the test antibody to the RSV-F molecule. In a second orientation, the test antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the reference antibody to the RSV-F molecule. If, in both orientations, only the first (saturating) antibody is capable of binding to the RSV-F molecule, then it is concluded that the test antibody and the reference antibody compete for binding to RSV-F. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antibody may not necessarily bind to the identical epitope as the reference antibody, but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope.

Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. (1990) 50:1495-1502). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art.

Immunoconjugates

The invention encompasses a human RSV-F monoclonal antibody conjugated to a therapeutic moiety (“immunoconjugate”), such as an agent that is capable of reducing the severity of primary infection with RSV and/or HMPV, or to ameliorate at least one symptom associated with RSV infection and/or HMPV infection, including coughing, fever, pneumonia, or the severity thereof. Such an agent may be a second different antibody to RSV-F and/or HMPV, or a vaccine. The type of therapeutic moiety that may be conjugated to the anti-RSV-F antibody and/or anti-HMPV antibody and will take into account the condition to be treated and the desired therapeutic effect to be achieved. Alternatively, if the desired therapeutic effect is to treat the sequelae or symptoms associated with RSV and/or HMPV infection, or any other condition resulting from such infection, such as, but not limited to, pneumonia, it may be advantageous to conjugate an agent appropriate to treat the sequelae or symptoms of the condition, or to alleviate any side effects of the antibodies of the invention. Examples of suitable agents for forming immunoconjugates are known in the art, see for example, WO 05/103081.

Multi-Specific Antibodies

The antibodies of the present invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004, Trends Biotechnol. 22:238-244. The antibodies of the present invention can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked {e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multi-specific antibody with a second binding specificity.

An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first and second Ig C_(H)3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig C_(H)3 domain binds Protein A and the second Ig C_(H)3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second C_(H)3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second C_(H3) include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.

Therapeutic Administration and Formulations

The invention provides therapeutic compositions comprising the inventive anti-RSV-F antibodies or antigen-binding fragments thereof. The administration of therapeutic compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol 52:238-311.

The dose of each of the antibodies of the invention may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When the antibodies of the present invention are used for treating a RSV infection and/or HMPV infection in a patient, or for treating one or more symptoms associated with a RSV infection and/or HMPV infection, such as the cough or pneumonia associated with a RSV infection and/or HMPV in a patient, or for lessening the severity of the disease, it is advantageous to administer each of the antibodies of the present invention intravenously or subcutaneously normally at a single dose of about 0.01 to about 30 mg/kg body weight, more preferably about 0.1 to about 20 mg/kg body weight, or about 0.1 to about 15 mg/kg body weight, or about 0.02 to about 7 mg/kg body weight, about 0.03 to about 5 mg/kg body weight, or about 0.05 to about 3 mg/kg body weight, or about 1 mg/kg body weight, or about 3.0 mg/kg body weight, or about 10 mg/kg body weight, or about 20 mg/kg body weight. Multiple doses may be administered as necessary. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. In certain embodiments, the antibodies or antigen-binding fragments thereof of the invention can be administered as an initial dose of at least about 0.1 mg to about 800 mg, about 1 to about 600 mg, about 5 to about 300 mg, or about 10 to about 150 mg, to about 100 mg, or to about 50 mg. In certain embodiments, the initial dose may be followed by administration of a second or a plurality of subsequent doses of the antibodies or antigen-binding fragments thereof in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.

Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings {e.g., oral mucosa, nasal mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. It may be delivered as an aerosolized formulation (See US Publ. No. 2011/031 1515 and U.S. Publ. No. 2012/0128669). The delivery of agents useful for treating respiratory diseases by inhalation is becoming more widely accepted (See A. J. Bitonti and J. A. Dumont, (2006), Adv. Drug Deliv. Rev, 58:1 106-118). In addition to being effective at treating local pulmonary disease, such a delivery mechanism may also be useful for systemic delivery of antibodies (See Maillet et al. (2008), Pharmaceutical Research, Vol. 25, No. 6, 2008).

The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see, for example, Langer (1990) Science 249:1527-1533).

In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

A pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present invention. Examples include, but certainly are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUIIVIALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™ OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but certainly are not limited to the SOLOSTAR™ pen (Sanofi-Aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.) and the HUMIRA™ Pen (Abbott Labs, Abbott Park, Ill.), to name only a few.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms.

Administration Regimens

According to certain embodiments, multiple doses of an antibody to RSV-F and/or HMPV may be administered to a subject over a defined time course. The methods according to this aspect of the invention comprise sequentially administering to a subject multiple doses of an antibody to RSV-F and/or HMPV. As used herein, “sequentially administering” means that each dose of antibody to RSV-F and/or HMPV is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the patient a single initial dose of an antibody to RSV-F and/or HMPV, followed by one or more secondary doses of the antibody to RSV-F and/or HMPV and optionally followed by one or more tertiary doses of the antibody to RSV-F and/or HMPV.

The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the antibody to RSV-F and/or HMPV. Thus, the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of antibody to RSV-F and/or HMPV, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of antibody to RSV-F and/or HMPV contained in the initial, secondary and/or tertiary doses vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses”).

In one exemplary embodiment of the present invention, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1 , 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21 , 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more) weeks after the immediately preceding dose. The phrase “the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of antibody to RSV-F and/or HMPV which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.

The methods according to this aspect of the invention may comprise administering to a patient any number of secondary and/or tertiary doses of an antibody to RSV-F and/or HMPV. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.

Accordingly, in certain embodiments are provided pharmaceutical compositions comprising: one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout and a pharmaceutically acceptable carrier and/or one or more excipients. In certain other embodiments are provided pharmaceutical compositions comprising: one or more nucleic acid sequences encoding one or more inventive antibodies or antigen-binding fragments thereof; or one or more the expression vectors harboring such nucleic acid sequences; and a pharmaceutically acceptable carrier and/or one or more excipients.

Therapeutic Uses of the Antibodies

Due to their binding to and interaction with the RSV fusion protein (RSV-F), it is believed that the inventive antibodies and antigen-binding fragments thereof are useful—without wishing to be bound to any theory—for preventing fusion of the virus with the host cell membrane, for preventing cell to cell virus spread, and for inhibition of syncytia formation. Additionally, as Applicant has demonstrated herein that, surprisingly, a subset of the inventive anti-RSV antibodies and antigen-binding fragment thereof display cross-neutralizing potency against HMPV, the inventive antibodies and antigen-binding fragments thereof are advantageous for preventing an infection of a subject with RSV and/or HMPV when administered prophylactically. Alternatively, the antibodies of the present invention may be useful for ameliorating at least one symptom associated with the infection, such as coughing, fever, pneumonia, or for lessening the severity, duration, and/or frequency of the infection. The antibodies of the invention are also contemplated for prophylactic use in patients at risk for developing or acquiring an RSV infection and/or HMPV infection. These patients include pre-term infants, full term infants born during RSV season (late fall to early spring), the elderly (for example, in anyone 65 years of age or older) and/or HMPV season, or patients immunocompromised due to illness or treatment with immunosuppressive therapeutics, or patients who may have an underlying medical condition that predisposes them to an RSV infection (for example, cystic fibrosis patients, patients with congestive heart failure or other cardiac conditions, patients with airway impairment, patients with COPD) and/or HMPV infection. It is contemplated that the antibodies of the invention may be used alone, or in conjunction with a second agent, or third agent for treating RSV infection and/or HMPV infection, or for alleviating at least one symptom or complication associated with the RSV infection and/or HMPV infection, such as the fever, coughing, bronchiolitis, or pneumonia associated with, or resulting from such an infection. The second or third agents may be delivered concurrently with the antibodies of the invention, or they may be administered separately, either before or after the antibodies of the invention. The second or third agent may be an anti-viral such as ribavirin, an NSAID or other agents to reduce fever or pain, another second but different antibody that specifically binds RSV-F, an agent (e.g. an antibody) that binds to another RSV antigen, such as RSV-G, a vaccine against RSV, an siRNA specific for an RSV antigen.

In yet a further embodiment of the invention the present antibodies are used for the preparation of a pharmaceutical composition for treating patients suffering from a RSV infection and/or HMPV infection. In yet another embodiment of the invention the present antibodies are used for the preparation of a pharmaceutical composition for reducing the severity of a primary infection with RSV and/or HMPV, or for reducing the duration of the infection, or for reducing at least one symptom associated with the RSV infection and/or the HMPV infection. In a further embodiment of the invention the present antibodies are used as adjunct therapy with any other agent useful for treating an RSV infection and/or and HMPV infectin, including an antiviral, a toxoid, a vaccine, a second RSV-F antibody, or any other antibody specific for an RSV antigen, including an RSV-G antibody, or any other palliative therapy known to those skilled in the art.

Accordingly, in certain embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout, such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In certain other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a nucleic acid sequence encoding one or more of the inventive antibodies or antigen-binding fragments thereof, such as nucleic acid sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic aci sequence, wherein such nucleic acid sequences is selected from the group consisiting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, or at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences or an expression vectors comprising such a nucleic acid sequence, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising such one or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least one symptom associated with RSV infection is treated, alleviated, or reduced in severity.

In certain embodiments ase provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout, such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 179, 188, 211, 221, or 229 as disclosed in Table 6.

In certain other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereo a nucleic acid sequence encoding one or more of the inventive antibodies or antigen-binding fragments thereof, such nucleic acid sequenced disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 179, 188, 211, 221, or 229 as disclosed in Table 6.

In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequences is selected from the group consisting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof of is selected from the group consisting of the antibodies designated as Antibody Number 179, 188, 211, 221, or 229 as disclosed in Table 6.

In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences or an expression vectors comprising such a nucleic acid sequence, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising suchone or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 179, 188, 211, 221, or 229 as disclosed in Table 6.

Combination Therapies

As noted above, according to certain embodiments, the disclosed methods comprise administering to the subject one or more additional therapeutic agents in combination with an antibody to RSV-F and/or HMPV or a pharmaceutical composition of the invention. As used herein, the expression “in combination with” means that the additional therapeutic agents are administered before, after, or concurrent with an antibody or pharmaceutical composition comprising an anti-RSV-F antibody. The term “in combination with” also includes sequential or concomitant administration of an anti-RSV-F antibody and a second therapeutic agent.

For example, when administered “before” the pharmaceutical composition comprising the anti-RSV-F antibody, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the pharmaceutical composition comprising the anti-RSV-F antibody. When administered “after” the pharmaceutical composition comprising the anti-RSV-F antibody, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after the administration of the pharmaceutical composition comprising the anti-RSV-F antibodies. Administration “concurrent” or with the pharmaceutical composition comprising the anti-RSV-F antibody means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the anti-RSV-F antibody, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the anti-RSV-F antibody.

Combination therapies may include an anti-RSV-F antibody of the invention and any additional therapeutic agent that may be advantageously combined with an antibody of the invention, or with a biologically active fragment of an antibody of the invention.

For example, a second or third therapeutic agent may be employed to aid in reducing the viral load in the lungs, such as an antiviral, for example, ribavirin. The antibodies may also be used in conjunction with other therapies, as noted above, including a toxoid, a vaccine specific for RSV, a second antibody specific for RSV-F, or an antibody specific for another RSV antigen, such as RSV-G.

Diagnostic Uses of the Antibodies

The inventive anti-RSV antibodies and antigen-binding fragments thereof may also be used to detect and/or measure RSV and/or HMPV in a sample, e.g., for diagnostic purposes. It is envisioned that confirmation of an infection thought to be caused by RSV and/or HMPV may be made by measuring the presence of the virus through use of any one or more of the antibodies of the invention. Exemplary diagnostic assays for RSV and/or HMPV may comprise, e.g., contacting a sample, obtained from a patient, with an anti-RSV-F and/or HMPV antibody of the invention, wherein the anti-RSV-F and/or HMPV antibody is labeled with a detectable label or reporter molecule or used as a capture ligand to selectively isolate the virus containing the F protein from patient samples. Alternatively, an unlabeled anti-RSV-F and/or HMPV antibody can be used in diagnostic applications in combination with a secondary antibody which is itself detectably labeled. The detectable label or reporter molecule can be a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, or ¹²⁵1; a fluorescent or chemiluminescent moiety such as fluorescein isothiocyanate, or rhodamine; or an enzyme such as alkaline phosphatase, β-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that can be used to detect or measure RSV containing the F protein and/or HMPV in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence-activated cell sorting (FACS).

Samples that can be used in RSV and/or HMPV diagnostic assays according to the present invention include any tissue or fluid sample obtainable from a patient, which contains detectable quantities of RSV-F protein and/or HMPV, or fragments thereof, under normal or pathological conditions. Generally, levels of RSV-F and/or HMPV in a particular sample obtained from a healthy patient (e.g., a patient not afflicted with a disease or condition associated with the presence of RSV-F and/or HMPV) will be measured to initially establish a baseline, or standard, level of the F protein from RSV and/or HMPV. This baseline level of RSV-F and/or HMPV can then be compared against the levels of RSV-F and/or HMPV measured in samples obtained from individuals suspected of having an RSV and/or HMPV infection, or symptoms associated with such infection.

EXAMPLES

Applicant has comprehensively profiled the human antibody response to RSV fusion protein (F) by isolating and characterizing 108 RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult donor, and used these antibodies to comprehensively map the antigenic topology of RSV F. The antibody response to RSV F was determined to be comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of RSV antibodies that target this region, as well as vaccine candidates that preserve the membrane-distal hemisphere of the preF protein. Additionally, this class of antibodies displayed convergent sequence features, thus providing a future means to rapidly detect these types of antibodies in human samples. Many of the antibodies that bound preF-specific surfaces from this donor were over 100 times more potent than palivizumab and several cross-neutralize human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of RSV vaccine and antibody-based therapeutic candidates, and offer new options for passive prophylaxis.

Large-Scale Isolation of RSV F-Specific Monoclonal Antibodies from Healthy Adult Human Donors

In order to comprehensively profile the human antibody response to RSV F, Applicant isolated and characterized approximately 108 monoclonal antibodies from the memory B cells of a healthy adult donor (“donor 003”). Although this donor did not have a documented history of RSV infection, healthy adults are expected to have had multiple RSV infections throughout life (26).

The magnitude of the memory B cell response in this donor to RSV F was assessed by staining peripheral B cells with a mixture of fluorescently labeled pre- and postfusion RSV F sorting probes (FIG. 6A through 6B) (11, 15). Both proteins were dual-labeled in order to eliminate background due to non-specific fluorochrome binding (27). Flow cytometric analysis revealed that 0.04-0.18% of class-switched (IgG⁺ and IgA⁺) peripheral B cells were specific for RSV F (FIG. 1A and Figure B), which is significantly lower than the percentage of RSV F-specific cells observed after experimental RSV infection and suggests that this donor was probably not recently exposed to RSV (28). Notably, index sorting showed that 17-38% of circulating RSV F-specific B cells express IgA, indicating that IgA memory B cells to RSV F are present in peripheral blood (FIG. 1B).

Approximately 200 RSV F-specific B cells were single-cell sorted from the donor sample, and antibody variable heavy (VH) and variable light (VL) chain genes were rescued by single-cell PCR (29). Over 100 cognate heavy and light chain pairs were subsequently cloned and expressed as full-length IgGs in an engineered strain of Saccharomyces cerevisiae for further characterization (30). Preliminary binding studies showed that approximately 80% of antibodies cloned from RSV F glycoprotein (F)-specific B cells bound to recombinant RSV F proteins.

Sequence Analysis of RSV F-Specific Antibody Repertoires

Sequence analysis of the isolated monoclonal antibodies revealed that the RSV-F specific repertoire was highly diverse, containing over 70 unique lineages (FIG. 1C and Table 2). This result is in stark contrast to the relatively restricted repertoires observed in HIV-infected patients (31), or in healthy donors after influenza vaccination (32). Compared to non-RSV-reactive antibodies (33), the RSV F-specific repertoires were skewed, generally, toward certain VH germline genes (VH1-18, VH1-2, VH1-69, VH2-70, VH4-304, and VH5-51) (FIG. 1D and Table 2) and longer heavy chain third complementarity-determining region (CDRH3) lengths (generally, approximately 14-18 amino acids in length; FIG. 1E and Table 2). Interestingly, a bias toward VH1-69 has also been observed in anti-HIV-1, anti-influenza, and anti-HCV repertoires (34-36), and recent studies have shown that there is a significant increase in the relative usage of VH1-18, VH1-2, and VH1-69 during acute dengue infection (37). Hence, it appears that these particular germline gene segments may have inherent properties that facilitate recognition of viral envelope proteins.

The average level of somatic hypermutation (SHM) ranged between 16 and 30 nucleotide substitutions per VH gene (excluding CDRH3) (FIG. 1F and Table 2), which is comparable to the average level of SHM observed in anti-influenza antibody repertoires (32, 38) and consistent with the recurrent nature of RSV infection (26). Interestingly, several antibodies contained 40 or greater VH gene nucleotide substitutions, suggesting that multiple rounds of RSV infection can result in antibodies with very high levels of somatic hypermutation (SHM).

A Large Proportion of Antibodies Bind Exclusively to preF

We next measured the apparent binding affinities of the IgGs to furin-cleaved RSV F ectodomains stabilized in the prefusion (DS-Cav1) or postfusion (F ΔFP) conformation using biolayer interferometry (11, 15). A relatively large proportion of the antibodies (36-67%) bound exclusively to preF (FIG. 2A and Figure B; Table 3). The vast majority of remaining antibodies bound to both pre- and postF, with only 5-7% of antibodies showing exclusive postF specificity (FIG. 2A and Figure B; Table 3). The low prevalence of postF-specific antibodies in these donor repertoires is consistent with the observation that less than 10% of anti-RSV F serum-binding activity specifically targets postF (8). Interestingly, however, the majority of cross-reactive antibodies bound with higher apparent affinity to postF (FIG. 2A; Table 3), suggesting that these antibodies were probably elicited by and/or affinity matured against postF in vivo. Hence, the significantly higher proportion of preF-versus postF-specific antibodies is likely due to the higher immunogenicity of the unique surfaces on preF compared to postF, rather than an increased abundance of preF in vivo. Finally, as expected based on the relatively high degree of sequence conservation between RSV subtypes, most of the antibodies showed binding reactivity to F proteins derived from both subtypes A and B (FIG. 2C; Table 3).

Since certain antiviral antibody specificities have been associated with poly- and autoreactivity (39-41), we also tested the RSV antibodies for polyreactivity using a previously described high-throughput assay that correlates with down-stream behaviors such as serum clearance (42, 43). One hundred and seventy-seven clinical antibodies, as well as several broadly neutralizing HIV antibodies, were also included for comparison. Interestingly, in contrast to many previously described HIV broadly neutralizing antibodies, the vast majority of RSV F-specific antibodies lacked significant polyreactivity in this assay (FIG. 2D).

RSV F-Specific Antibodies Target Six Major Antigenic Sites

To map the antigenic specificities of the RSV F-specific antibodies, Applicant first performed competitive binding experiments using a previously described yeast-based assay (44). Antibodies were initially tested for competition with D25, AM14 and MPE8—three previously described preF-specific antibodies (10, 17, 21)—and motavizumab, an affinity-matured variant of palivizumab that binds to both pre- and postF (10, 11, 45). Non-competing antibodies were then tested for competition with a site IV-directed mAb (101F) (46), a site I-directed antibody (Site I Ab), and two high affinity antibodies (High Affinity Ab I and High Affinity Ab 2, respectively) that did not strongly compete with each other or any of the control antibodies. Each antibody was assigned a bin based on the results of this competition assay (see, e.g., Table 4).

In order to confirm and increase the resolution of our epitope assignments, the binding of each antibody to a panel of preF variants was measured using a luminex-based assay. Each variant contained 2-4 mutations clustered together to form a patch on the surface of preF. A total of nine patches that uniformly covered the surface of preF were generated (FIG. 7A through FIG. 7C). Deglycosylated preF was also included to identify antibodies targeting glycan-dependent epitopes. Binding of each antibody to the 10 preF variants was compared to that of wild-type preF and used to assign a patch (see, e.g., Table 4). Previously characterized antibodies D25, AM14 and motavizumab were used to validate the assay (see, e.g., FIG. 7C and Table 4). The combined bin and patch data were then used to assign each antibody to a single antigenic site (FIG. 3A through FIG. 3G), which were defined based on previously determined structures, resistance mutations, and secondary structure elements of the F protein. Overall, these data show that the large majority of isolated antibodies target six dominant antigenic sites on prefusion RSV F (Ø, I, II, III, IV, and V). Interestingly, only a small proportion of the isolated antibodies had binding profiles similar to that of AM14, suggesting that antibodies targeting this quaternary epitope are not commonly elicited during natural infection. None of the antibodies were sensitive to deglycosylation of F, demonstrating that glycan-dependent antibodies are also rarely elicited by natural RSV infection.

Analysis of the preF- and postF-binding activities of the antibodies targeting each antigenic site (see, e.g., FIG. 3C through FIG. 3G; Table 4) revealed that three sites are primarily found on preF (Ø, III, and V). Antibodies targeting site Ø and site III have been previously described (10, 17), and these sites are located on the top and side of the preF spike, respectively. Greater than 20% of the antibodies from this donor recognized site Ø and approximately 22% recognized site III. A relatively large proportion of antibodies from this donor (approximately 14%) recognized the third preF-specific site, which has not been previously described and therefore has been designated herein as region site V (See, e.g., FIG. 3C through FIG. 3G; Table 4). The majority of site V antibodies competed with D25, MPE8 and motavizumab, which was unexpected given the distance between the epitopes recognized by these three antibodies. The patch mutant analysis revealed that these antibodies interact with the α3 helix and β3/β4 hairpin of preF. This region is located between the epitopes recognized by D25, MPE8, and motavizumab, explaining the unusual competition profile observed for this class of antibodies (See, e.g., FIG. 8). In addition to the three primarily preF-specific sites, a large number of the antibodies that recognized antigenic site IV were preF-specific, likely due to contacts with β22, which dramatically rearranges during the transition from pre- to postF. In summary, the epitope mapping data show that the large majority of isolated antibodies target six dominant antigenic sites, approximately half of which are exclusively expressed on preF.

Highly Potent Neutralizing Antibodies Target preF-Specific Epitopes

The antibodies were next tested for neutralizing activity against RSV subtypes A and B using a previously described high-throughput neutralization assay (15). Greater than 60% of the isolated antibodies showed neutralizing activity, and approximately 20% neutralized with high potency (IC₅₀≤0.05 μg/ml) (see, e.g., FIG. 4A and FIG. 4B; Table 3). Notably, several clonally unrelated antibodies were ≥5.0-fold more potent than D25 and ≥100-fold more potent than palivizumab (see, e.g., FIG. 4A; Table 3). Interestingly, there was no correlation between neutralization potency and level of SHM, suggesting that extensive SHM is not required for potent neutralization of RSV. Consistent with the binding cross-reactivity data, the majority of neutralizing antibodies showed activity against both subtype A and B (FIG. 4A through FIG. 4C; Table 3).

The relationship between preF- and postF-binding affinity and neutralization potency was next investigated, which clearly demonstrated that the majority of highly potent antibodies bound preferentially or exclusively to preF (see, e.g., FIG. 4D through FIG. 4G; Table 3). Quantifying this difference revealed that more than 80% of highly potent antibodies (IC₅₀<0.05 μg/ml) were specific for preF (See, e.g., FIG. 9; Table 3) and that the median IC₅₀ for preF-specific antibodies was more than 8-fold lower than for pre- and postF cross-reactive antibodies and 80-fold lower than antibodies that specifically recognized postF (see, e.g., FIG. 4E; Table 3). Importantly, there was a positive correlation between preF binding and neutralization (P<0.001, r=0.24), and the apparent preF K_(D)s generally corresponded well with the neutralization IC₅₀s (see, e.g., FIG. 5A; Table 3). In contrast, there was no correlation between neutralization potency and postF affinity (P=0.44, r=−0.07) (see, e.g., FIG. 5B; Table 3). This result is compatible with the occupancy model of antibody-mediated neutralization (47), and suggests that DS-Cav1 is a faithful antigenic mimic of the native preF trimer. Notably, very few antibodies neutralized with IC₅₀s lower than 100 pM, which is consistent with the previously proposed ceiling to affinity maturation (48, 49).

The relationship between neutralization potency and antigenic site was next analyzed. The results, provided in, e.g., FIG. 5C, Table 3, and Table 4, collectively, indicated that over 60% of the highly potent neutralizing antibodies targeted antigenic sites Ø and V, which are two of the three prefusion-F specific sites. In contrast, antibodies targeting sites III and IV showed a wide range of neutralization potencies, and antibodies targeting sites I and II were generally moderate to non-neutralizing. Similar results were obtained using binding affinities and neutralization potencies measured for subtype B (See, e.g., FIG. 10A through FIG. 10C; Table 3 and Table 4). Interestingly, a subset of site IV-directed antibodies neutralized with substantially lower potency than would be expected based on preF binding affinity (see, e.g., FIG. 5A; Table 3). This result may suggest that certain epitopes within site IV are less exposed in the context of the native envelope spike expressed on the crowded surface of the virion than on recombinant preF.

Several Antibodies Cross-Neutralize RSV and HMPV

Given that the RSV and human metapneumovirus (HMPV) F proteins share 33% amino acid identity, and certain RSV F-specific antibodies cross-neutralize HMPV (17, 50), the antibodies from this donor were tested for neutralizing activity against HMPV. Of the 108 antibodies tested, five neutralized HMPV and two showed highly potent activity against both HMPV and RSV (see, e.g., Table 5). Sequence analysis revealed that the five antibodies represent two different clonal families, which utilize different VH germline genes and have varying CDRH3 lengths and levels of somatic hypermutation (See, e.g., Table 2 and sequence listing). All of the cross-neutralizing antibodies bound exclusively to preF and competed with MPE8 (See, e.g., Table 5), in agreement with previous studies indicating that MPE8 cross-neutralizes four pneumoviruses, including RSV and HMPV (17). This result suggests, inter alia, that highly conserved epitopes are relatively immunogenic in the context of natural RSV and/or HMPV infection.

Affinity Maturation of RSV F-Specific Antibodies:

Some embodiments refer to affinity matured antibodies of any of the antibodies listed in Table 6 (each understood as a “parent” antibody” for producing an affinity matured variant). Affinty matured antibodies may be produced by mutagenesis of any one or more of the CDRs of the parent antibody. According to a specific embodiment, the invention provides for affinity matured variants comprising one or more point mutations e.g., 0, 1, 2, or 3 point mutations in each of the CDR sequences, of any of the antibodies listed in Table 6, or of an antibody comprising the six CDR sequences of any of the antibodies listed in Table 6. Affinity matured variants can be produced by any affinity maturation method employing standard mutagenesis techniques, e.g., for optimizing the binding characteristics, such as increasing affinity of binding, or increasing Kon, or decreasing Koff, and can be characterized by a K_(D) difference of at least 2 fold, 5 fold, 1 log, or 2 logs, or 3 logs, as compared to the parent antibody. Such affinity matured antibodies still have the same binding specificity as the parent antibody and e.g., an optimized affinity of binding the target epitope.

Selected anti RSV antibodies were identified for affinity maturation. Oligos were ordered which comprised CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences that were variegated via NNK diversity. The NNK oligos were incorporated into the parent HC or LC via DNA shuffling, as described previously (Stemmer W P et al., DNA shuffling by random fragmentation and reassembly: In vitro recombination for molecular evolution. Proc Natl Acad Sci U S A. 1994 Oct. 25; 91(22):10747-51). The library was then created by transforming the VH and VL PCR products into yeast already containing either the light chain or heavy chain plasmid of the parent. The diversified libraries were then selected using flow cytometry. For each FACS round, the libraries were affinity pressured using decreasing amounts of antigen and clones with improved binding affinities were sorted and propagated. Once improved binding populations were observed by flow cytometry (typically two rounds of selection), single yeast clones were be picked for sequencing and characterization (Table 6).

A specific embodiment refers to affinity matured variants of the antibodies 128, 133 and 227 in Table 6. Notably, the antibodies numbered 232 and 233 are affinity matured variant of the antibody numbered 128 in Table 6, the antibodies numbered 234-236 are affinity matured variant of the antibody numbered 133 in Table 6 and the antibodies numbered 237-244 are affinity matured variant of the antibody numbered 227 in Table 6

Antibody Production and Purification of Affinity Matured Antibodies

Yeast clones were grown to saturation and then induced for 48 h at 30° C. with shaking. After induction, yeast cells were pelleted and the supernatants were harvested for purification. IgGs were purified using a Protein A column and eluted with acetic acid, pH 2.0. Fab fragments were generated by papain digestion and purified over KappaSelect (GE Healthcare LifeSciences).

RSV In Vitro Neutralization in ELISA based Microneutralization Assays

In vitro RSV neutralization was tested in ELISA based Microneutralization Assays using RSV-A strain A2 (ATCC, VR1540P). Virus (at a final multiplicity of infection of approximately 0.25) was added to 96-well plates containing serially diluted mAbs in serum-free MEM and pre-incubated for 30 min at 4° C. Freshly trypsinized Hep-2 cells (1.5×10E⁴ cells/well) were then added to each well in MEM supplemented with 5% FCS. Following incubation for 4 days at 37° C. and 5% CO₂, medium was aspirated and cells were washed twice with 200 μl PBS/well, air-dried and fixed with 100 μl Acetone (80%). RSV replication was measured by quantification of expressed viral proteins by ELISA. For this purpose, fixed cells were washed 2×times with PBS-0.1% Tween-20, blocked with 1% skimmed milk in PBS for 1 hour at RT and then stained with a polyclonal goat-anti RSV antibody preparation (BioRad, #7950-0004) for 1 hour at RT in blocking buffer. A donkey anti-goat IgG HRP conjugate was used as detection reagent and 1 step-Ultra TMB (Thermo Fisher Scientific, #34209) as substrate. % inhibition of virus replication was calculated relative to control cells infected with virus in absence of neutralizing antibodies. An isotype matched control mAb was included in all experiments. mAb potency is expressed as half-maximal inhibitory concentration that resulted in 50% reduction in virus replication (IC₅₀). Results are provided in FIG. 11 and demonstrate that all mAbs were able to neutralize RSV-A2 in this setting, with a broad range of IC₅₀ values ranging from 8.5 ng/ml (ADI-31674) to 495.5 ng/ml (ADI-31379).

Discussion

An in-depth understanding of the human antibody response to RSV infection will aid the development and evaluation of RSV vaccine and therapeutic and/or prophylactic antibody candidates for the treatment and/or prevention of RSV infection. Although previous studies have coarsely mapped the epitopes targeted by RSV-specific neutralizing antibodies in human sera (4, 8), the specificities and functional properties of antibodies induced by natural RSV infection have remained largely undefined. As disclosed herein, preF- and postF-stabilized proteins (11, 15), a high-throughput antibody isolation platform, and a structure-guided collection of prefusion F mutants, were used to clonally dissect the human memory B cell response to RSV F in a naturally infected adult donor, and highly potent and selective RSV-neutralizing—as well as highly potent anti-RSV/anti-HMPV cross-selective and cross-neutralizing—were isolated and characterized.

In the repertoire analyzed, the ratio of preF-specific antibodies to those that recognize both pre- and postF was slightly greater than 1:1 (See, e.g., FIG. 2B). These values are somewhat lower than those reported for human sera, which showed approximately 70% of anti-F serum binding is specific for preF (8). This discrepancy may be the result of differences between the levels of individual antibodies in serum, differences in the B cell phenotypes achieved for a particular specificity, or variation between donors. Despite these minor differences, the results of both studies suggest that preF-specific epitopes and epitopes shared by pre- and postF are immunogenic during natural RSV infection, whereas the unique surfaces on postF are significantly less immunogenic.

The repertoire analysis disclosed herein revealed that the large majority of RSV F-specific antibodies target six dominant antigenic sites on prefusion RSV F: Ø, I, II, III, IV, and V. These sites were defined based on previously determined structures, epitope binning/competition assays, resistance mutations, and secondary structure elements of the preF protein. It is important to note that the nomenclature for describing RSV F antigenic sites has evolved over time (6, 51-57), and previous mapping efforts were based on the postfusion conformation of F and did not include surfaces present exclusively on preF. The crystal structure of preF has provided critical information about F structure and function as well as new reagents to map antibody binding sites on the unique surfaces of preF and surfaces shared with postF. To a first approximation, each antibody can be assigned primarily to one of these sites. However, it is likely that antibody epitopes cover the entire surface of F and that there are antibodies that bind two or more adjacent antigenic sites within a protomer and quaternary antibodies that bind across protomers.

Importantly, the results disclosed herein show that the most potently neutralizing antibodies target antigenic sites Ø and V, both of which are located near the apex of the preF trimer. These findings are consistent with results obtained from human sera mapping, which determined that the majority of neutralizing activity can be removed by pre-incubation with preF (4, 8) and that preF-specific sites other than site Ø make up a considerable fraction of preF-specific neutralizing antibodies (8). Although antigenic site Ø has been shown to be a target of potently neutralizing antibodies (8, 10), the interaction of antibodies with site V is less well understood. Interestingly, it was found that the majority of site V-directed antibodies share several convergent sequence features, suggesting that it may be possible to rapidly detect these types of antibodies in human samples using high-throughput sequencing technology (58). Applicant anticipates this finding to be particularly advantageous in profiling antibody responses to RSV vaccine candidates that aim to preserve the apex of the preF trimer.

The extensive panel of antibodies described here provides new opportunities for passive prophylaxis, as well as for treatment of RSV infection. A large number of these antibodies neutralize RSV more potently than D25, which serves as the basis for MEDI8897—a monoclonal antibody that is currently in clinical trials for the prevention of RSV in young, at risk children (59). Additionally, a sub-set of these antibodies were demonstrated to cross-neutralize HMPV.

The development of an effective RSV vaccine has presented a number of unique challenges, and selection of the optimal vaccination strategy will be of the utmost importance. The in-depth analysis of the human antibody response to natural RSV infection presented here provides insights for the development of such a vaccine. Importantly, the results suggest that immunization of pre-immune donors with preF immunogens would be expected to boost neutralizing responses, whereas the use of postF immunogens would likely expand B cell clones with moderate or weak neutralizing activity. Similarly, immunization of RSV naive infants with preF immunogens would be expected to activate naive B cells targeting epitopes associated with substantially more potent neutralizing activity compared to postF immunogens. In addition, the ideal RSV vaccine should preserve antigenic sites Ø and V, since these sites are targeted by the most highly potent antibodies elicited in response to natural RSV infection.

Accordingly, disclosed herein are highly selective and potent anti-RSV antibodies, as well as highly potent cross-neutralizing anti-RSV and anti-HMPV antibodies, as well as vaccine candidates, for the treatment and or prophylaxis of RSV and/or HMPV infection. Additionally, the reagents disclosed here provide a useful set of tools for the evaluation of clinical trials, which will be critical for selecting the optimal RSV vaccination or antibody-based therapeutic strategy from the many currently under investigation (60).

TABLE 1 Antigenic sites targeted by prototypic RSV antibodies Antigenic site Prototypic antibodies Ø D25, 5C4, AM22 (10, 16) I 131-2a, 2F II 1129, palivizumab, motavisumab (6) III MPE8 (17) IV 101F (57), mAb 19 (19)

TABLE 2 Germline usage and sequence information of anti-RSV antibodies VH LC Number of Number of Anti- germ- germ- nucleotide nucleotide body line line substi- substi- number gene gene CDR H3 CDR L3 Lineage tutions tutions Name (Ab #) usage usage Sequence Sequence number in VH in VL ADI- 124 VH2-70 VK1-39 ARTHIYDSSG QQSYSSP 68  7 10 15005 YYLYYFDY WT ADI- 125 VH4- VK1-39 ARGKYYDRG QQSYSTP 51 17 10 15006 304 GYYLFYLDY IFT ADI- 126 VH3-15 VL1-40 TTDRGITARPI QSYDGG 82 15  9 15555 FDS LSGYV ADI- 127 VH1-69 VL1-40 ARDLDYDILT QSCDSSL 28 12  1 15556 GYSVNYYYY SGWV GMDV ADI- 128 VH1-69 VL3-21 ASLRYFDWQ QVWDTI 73  6  6 15557 PGGSYWFDP DDHKDG L ADI- 129 VH1-18 VL3-1 ARDYIVAIVA QAWDSSI 43 12 11 15558 ALPHGMDV RV ADI- 130 VH1-69 VK3-20 ATDSYYVWT QQYGSW 76 30 21 15559 GSYPPPFDL PLT ADI- 131 VH3-30 VL3-21 ARDPLGIGVK QVWDSIS 32 17  9 15560 GYVDF DHLV ADI- 132 VH1-69 VK1-39 ARSPPFWSDY QQSYTTP 66  8  8 15561 SRGWFDP WT ADI- 133 VH5-51 VK1-33 ATQGLEGAF QHYDSFP 77 21 10 15562 DY IFT ADI- 134 VH3-9 VK3-15 VKDGYTSSW QQYNNW 85  7  8 15563 HSDYHYGLD PLT V ADI- 135 VH1-69 VK3-20 ARDNYYVWT QQYGSTP 29 16 12 15564 GRYPEFDF IT ADI- 136 VH1-8 VL1-40 VYNFWSDSS QSYDSSL 89 18  9 15565 VS RGYV ADI- 137 VH1-18 VK2-30 ARESGVAAA MQGIYW 48 11  2 15566 ATLLY PRT ADI- 138 VH1-46 VK1-39 GREDSYCSG QQTYSTP 78 24  8 15568 DSCFNSGSGR HT WVDS ADI- 139 VH1-18 VK2-30 ARDPGVTAA LQGTPPY 30  8  4 15569 VLLDY T ADI- 140 VH3-30 VK1D- ARGRTSHINT QQYYSLP 54 15 14 15570 8 PETK WT ADI- 141 VH1-2 VL1-51 ARDVLWLNG GTWDSSL 41 10  4 15571 F STGPYVV ADI- 142 VH1-46 VK1-9 ARARIQLWA QQLNRYP 20 14  7 15572 PNYYGMDV LT ADI- 143 VH1-18 VL3-21 ARADGGSGS QLWDSSS 14 16  5 15573 YYSA DSHV ADI- 144 VH3-21 VL1-40 ARAPLLPAM QSYDRSL 17 18  3 15574 MDL NGYV ADI- 145 VH1-8 VL1-40 VYDFWSDDS QSFDSSL 89 50 10 15575 VK RGYV ADI- 146 VH5-51 VL1-44 ARHSSPYSSG AAWDDS 58 13  6 15576 WYGDTYFFD LRGYV S ADI- 147 VH1-69 VL2-14 ARGVFRVGC SSYSSSST 56  4 13 15577 SDTSCLKNY LVV YGTDV ADI- 148 VH3-48 VK3-11 ARDAGPVWS QQRYNW 23  9  4 15578 GYYDYGMD PPLT V ADI- 149 VH3-9 VK1-39 AKTDGAVAV QQSYIAP 10  5  6 15579 DGPFDY PT ADI- 150 VH1-69 VK3-11 AGAPYPMDV QQRTNW  1  9  3 15581 QGLS ADI- 151 VH1-18 VK1-39 ARRYDILTGG QQSYSTP 65  8  4 15582 GWFDS LS ADI- 152 VH5-51 VK3-20 ARQDNSGWA QQYDSSP 64  8  5 15583 DFFPFDY WT ADI- 153 VH3-30 VL1-47 ARDPLFLYN SVWDDS 31 17  6 15586 YEPFDY LNGRL ADI- 154 VH3-20 VK1-9 ARVGGITKW QHLNSYP 69  8  6 15587 WYYGMDL LT ADI- 155 VH4-61 VK3-20 ARDVGSTPY QQFGRSP 40 20 13 15588 NYYGMDV ELT ADI- 156 VH4-34 VL2-14 ARAPWYTHA SSYTNSN 19  9  6 15589 MDV TLGV ADI- 157 VH3-43 VK1-33 AKTKYRGTY QQYDNL 11 13  1 15590 YYFDS PPVT ADI- 158 VH3-21 VL1-40 AREDYDSRV QSYDSSR 45 11  2 15591 YYLKWFDP SGYV ADI- 159 VH3-15 VL1-40 TTDRGITARPI QSYDGG 82 16  9 15592 FDS LSGYV ADI- 160 VH3-21 VK2-28 ARYFGDYSG MQALQT 72 15  4 15593 LGNYYYYGM PR DV ADI- 161 VH3-48 VK1-39 ARDFPPINLA QQSYSTS 26  6  4 15594  ATTRNYYYY YT VMDV ADI- 162 VH2-5 VL3 -21 TYARYSSALF QVWESS 83 13  6 15595 GGYYFHS GDHPRI ADI- 163 VH3-15 VL1-40 TTDRGITARPI QSYDGG 82 18 10 15596 FDS LSGYV ADI- 164 VH3-21 VL1-40 ARADYDRSV QSYDSSL 15  5  3 15597 YHLNWFDP SGTWV ADI- 165 VH3-49 VL6-57 TMAVVVPGA HSYDSSN 81  3  5 15599 TDAFDI PWV ADI- 166 VH3-53 VK3-20 ARELVPNFYE QQYGFSQ 46 10  5 15600 SHGYFSV T ADI- 167 VH3-23 VK3 -15 AKDADFWSG QQYNQW  2 25  6 15601 EAYNGGYNF PPIT DS ADI- 168 VH3-30 VK3-20 AKDLAWIFG QQYGSSP  6 10  2 15602 LGASYMDV FGLT ADI- 169 VH3-23 VK3-15 ARSWDDYGD QQYSDW 67 24  6 15603 LDWYFAL PPLT ADI- 170 VH3-11 VL1-40 ARFPLYCSRS QSYDRSL 50  8  4 15604 SCSHYVDY SVV ADI- 171 VH5-51 VL6-57 ARFEYGDFGF QSYDSSN 49 11  2 15605 HRV ADI- 172 VH3-23 VK3-15 AKSWDDYGD QQYSDW  9 16  5 15606 LDWYFAL PPLT ADI- 173 VH3-23 VL2-11 AKELREYYY CSYAGTY  8  5  2 15607 DSSGFDY TYV ADI- 174 VH3-30 VK1-39 ASQGYHYVN QQSYMT 74 17 12 15609 MADVGVPSF PPT DH ADI- 175 VH1-69 VK1-39 AKTVSQYPN LQTYSTP 12  8  6 15610 TYNYGMDV LT ADI- 176 VH1-69 VK3-11 ARVPPPRGHC QLRDYW 71 12  4 15611 ESTSCLWGT PPTWT YFAF ADI- 177 VH3-48 VK1-39 ARDQYIWNY LQDHTCP 34 12 12 15612 VEPLDY WT ADI- 178 VH1-69 VK3-11 ARDRGNNGR QQRNNW 36 17  3 15613 YYAMDV PPT ADI- 179 VH3-21 VL1-40 ARAPLLPAM QSYDRSL 17 16  3 15614 MDL NGYV ADI- 180 VH3-21 VL1-40 ARADYDRSV QSYDSSL 15  5  3 15615 YHLNWLDP SGTWV ADI- 181 VH3-11 VK3-20 ARDRNWGY QLYGNSR 37  5  4 15616 AYGSDY T ADI- 182 VH3-23 VK1-33 AKDDPTLFW QQYDNL  4 45 11 15617 SGSGYYGMD PLT V ADI- 183 VH3-53 VK3-11 ARMETVTTD QQHRDW 63 44 12 15618 AGSGWDWY RPVT FEV ADI- 184 VH1-8 VL1-40 VYNFWSDSS QSFDSSL 89 17 11 15619 VS RGYV ADI- 185 VH1-8 VL3-1 AREARDLRV QAWDSSI 44  6  7 15620 GATNFDY DVV ADI- 186 VH1-69 VK3-20 ARDNYYVWT QQYGSTP 29 21 17 15621 GHYPEFDF IT ADI- 187 VH3-23 VK1-12 ARIVIVGVLR QQANSFP 60 16  7 15622 FQEWLSSDG FT MDV ADI- 188 VH3-21 VL1-40 ARAPLLPAM QSYDRSL 17 17  3 15623 MDL NGYV ADI- 189 VH3-11 VL1-40 ARIRPDDSSG QSYDSSL 59  8  2 15624 YPDY SGFV ADI- 190 VH1-46 VL3-1 ARDRAGCSG QAWDSR 35  6  2 15625 GSCYYYGMD TVV V ADI- 191 VH1-69 VK1-5 ARERYPSTDD QQYNSIP 47 11  9 15626 YYRSGRYYG VT E ADI- 192 VH3-30 VL3-21 AKDRGSIWN QVWDASI  7  6  5 15627 VGDGMDV GPLYV ADI- 193 VH3-30 VL2-14 ARDAVPHYD SSYTSFTP 24 15  4 15628 YVWGNFDY VV ADI- 194 VH3-23 VK3-15 AKDADFWSG QQYNKW  2 20  3 15629 DSYNGGYNF PPLT DS ADI- 195 VH3-11 VK1-33 AQGWYSDF QQNDNL 13  8  5 15630 WSGPIRI VLT ADI- 196 VH3-9 VK3-15 AKDAHYFDN QQYNNW  3  5  6 15631 SGHYYYGLD PLT V ADI- 197 VH3-49 VK2-28 SGASRGFWS MQPLQTT 79 16 10 15632 GPTYYYFGM DV ADI- 198 VH5-51 VL6-57 ARLRLHPQSG QSYDNAI 62 18  8 15633 MDV WV ADI- 199 VH1-69 VK3-11 ARDRSVTPR QHRSNW 38  1  0 15634 YYGMDV PPLT ADI- 200 VH3-21 VL1-40 ARAPLLPAM QSYDRSL 17 16  3 15635 MDL NGYV ADI- 201 VH1-69 VK1-9 ARLAGPRWP QQLNSFP 61  8  0 15636 GYGMDV LT ADI- 202 VH1-24 VK1-39 SSVGPAGWF HQSYIPPF 80 15  3 15637 DP T ADI- 203 VH3-21 VL1-40 VRDSGHQDY QSYDRSL 88  7  5 15638 RGDY SGWV ADI- 204 VH2-70 VK1 -39 ARASLYDSG QLSYSSL 21  6  7 15640 GYYLFFFDY WT ADI- 205 VH3-30 VL2-14 AKDGYLAPD SSYTSSS  5 12  8 15641 F GQA ADI- 206 VH3-53 VK1-27 ARDDYDFWS QKYNSVP 25  3  1 15642 GNGPPEMAV LT ADI- 207 VH5-51 VK3-20 ARQDDSGWA QQYDSSP 64  8  6 15643 DFFPFDY WT ADI- 208 VH1-69 VK1-5 ARDSPKISAT QHYDSYS  9  8  6 15644 EYYFDY GT ADI- 209 VH3-23 VK1-12 ARGYHIDWF QQAKSLP 57 13  8 15645 DF RT ADI- 210 VH3-53 VK3-20 ARAGVVGED QQYGGSP 16 16  9 15646 RSGWYGPDY YT FHGLDV ADI- 211 VH1-69 VK3-11 ARVGLGRTW QHRTNW 70 15  4 15647 IYDTMGYLD PSLT Y ADI- 212 VH3-21 VL1-40 ARAPLLPAM QSYDRSL 17 16  3 15648 MDL NGYV ADI- 213 VH3-21 VL1-40 VRDHCTGGS QSYDSSL 87  9  2 15649 CYLNGMDV SGSV ADI- 214 VH3-53 VK1-27 ARDDYDFWS QKYDSVP 25  2  4 15650 GNGPPEMAV LT ADI- 215 VH2-70 VK1-39 ARTNRYDKS QQSYSSF 68 28 14 15651 GYYLYYLDY FT ADI- 216 VH3-30 VL2-14 ARDAVPHYD SSYTSFTP 24 16  3 15652 YVWGNFDY VV ADI- 217 VH1-69 VL3-21 ARGSGGSNA QVWDSR 55 14  8 15653 YFDP SDHPYV ADI- 218 VH1-69 VL2-14 VRDERNGGY SSYTISST 86 51  8 15654 LV ADI- 219 VH3-30 VK2-28 ARDYIHGDY MQPLQTI 42  7  0 15655 GLDV T ADI- 220 VH1-2 VL1-40 ASRSWDHDA HCYDSRL 75  6  3 15656 FDI SVV ADI- 221 VH1-69 VK3-11 ARVGVGRTW QHRSDW 70 12  3 15657 IYDTMGYLD PSLT F ADI- 222 VH3-9 VL1-47 VKDGTPIAVA AVWDDS 84 10  8 15658 GYFEY LSCYV ADI- 223 VH1-69 VL3-21 ARCPPFEGVR QVWETSS 22 10 15 15659 PPWFDP DHPV ADI- 224 VH5-51 VL6-57 ARGPFPHYFD QSYDPTN 52 23  4 15660 S QNV ADI- 225 VH3-30 VL3-21 ARAPVTGAS QVWDST 18 20  6 15661 YYLDY SDHLV ADI- 226 VH4-61 VK3-11 ARDIGEDKY QQRTNW 27  2  2 15662 GTYYGMDV PPVT ADI- 227 VH3-21 VL1-40 ARDQPGTIFG QSYDSRL 33 12  1 15663 VVQDY SVV ADI- 228 VH1-69 VK3-11 ARDRTTAVR QHRANW 38  8  2 15664 YYAMDV PPLT ADI- 229 VH1-69 VK3-11 ARVGVGRTW QHRNNW 70 20  6 15665 VYDIMGYLD PSLT Y ADI- 230 VH4-34 VK3-15 ARGRGYYGS QQYNNW 53 22  9 15666 TTDYRGLHW PRT FDP ADI- 231 VH3-66 VK3-15 KDADFWSG QQYHNW  2 20  4 15667 AAYNGGYNF PPLT DS

TABLE 3 Affinity and Neutralization data for anti-RSV antibodies Neut IC₅₀ Antibody Prefusion Postfusion Prefusion Postfusion (ug/ml) Neut IC₅₀ number subtype A K_(D) subtype A K_(D) subtype B K_(D) subtype B K_(D) subtype (ug/ml) Name (Ab #) (M)* (M)* (M)* (M)* A* subtype B* ADI- 124 1.398E−09 2.36714E−10  1.3986E−09 2.52685E−10 2.159 2.533 15005 ADI- 125 3.59777E−09   2.43013E−10     4.2E−09   3.611E−09 19.150 >10 15006 ADI- 126 NB NB 2.188 2.454 15555 ADI- 127 1.846E−09 2.46853E−10   2.199E−09 1.90295E−10 0.055 0.081 15556 ADI- 128 1.34048E−10   NB   6.096E−10 NB 0.041 0.028 15557 ADI- 129 1.564E−09 NB   9.401E−10 NB 15558 ADI- 130 8.65801E−10   NB 9.80392E−10 NB 0.008 0.006 15559 ADI- 131 2.666E−08 NB NB NB 15560 ADI- 132 5.5991E−09    5.907E−10    8.62E−09   1.083E−09 5.626 22.430 15561 ADI- 133 1.8315E−10  NB NB NB 0.010 15562 ADI- 134 2.50407E−10   NB     2.2E−09 NB 0.014 0.047 15563 ADI- 135 7.249E−10 NB     6.4E−10 NB 0.011 0.016 15564 ADI- 136 1.6835E−09  NB 6.75676E−09 NB 21.290 6.250 15565 ADI- 137 2.7137E−10  NB 2.64236E−10 NB 0.010 0.043 15566 ADI- 138 4.92247E−10   NB 6.99301E−10 NB 0.016 0.033 15568 ADI- 139 3.07267E−10   NB 2.49906E−10 NB 0.006 0.035 15569 ADI- 140 8.70322E−09   NB NB NB 13.350 >10 15570 ADI- 141 2.30229E−09   NB   2.568E−08 NB 0.541 0.430 15571 ADI- 142 3.8994E−09  NB NB NB 9.480 6.250 15572 ADI- 143 NB  1.9802E−10 NB 1.98807E−10 6.250 1.670 15573 ADI- 144 4.0347E−10  NB 4.59982E−10 NB 0.176 0.226 15574 ADI- 145 3.06466E−09   NB 4.16146E−09 NB >10 1.473 15575 ADI- 146 NB 2.36939E−10 NB 1.79211E−10 6.076 9.855 15576 ADI- 147 5.80215E−09   7.78816E−10 4.65658E−09   6.788E−10 >10 >10 15577 ADI- 148 NB   1.268E−09 NB   1.536E−09 15578 ADI- 149 NB NB 8.021 >10 15579 ADI- 150 5.56328E−09   NB NB NB 8.249 6.125 15581 ADI- 151 4.40238E−09    3.8506E−10 2.32099E−09 2.94942E−10 2.216 6.738 15582 ADI- 152 3.65965E−10   NB  3.5137E−10 NB 0.443 0.377 15583 ADI- 153 2.80387E−09   NB 5.78202E−09 NB >10 1.020 15586 ADI- 154 1.62602E−09   NB 2.41838E−09 NB >10 0.130 15587 ADI- 155 2.71998E−10     3.526E−10   4.266E−10   9.527E−10 0.094 0.234 15588 ADI- 156 NB NB NB NB 0.876 18.510 15589 ADI- 157 2.273E−08 NB NB NB >10 >10 15590 ADI- 158 2.49844E−10   NB 3.04044E−10 NB 0.086 0.219 15591 ADI- 159 NB    4.82E−08 12.300 20.900 15592 ADI- 160 4.19024E−09   5.07228E−10 3.95413E−09 7.60746E−10 >10 >10 15593 ADI- 161 4.92005E−10   NB 5.48847E−10 NB 3.250 3.280 15594 ADI- 162 8.89284E−10   NB NB NB 0.020 0.170 15595 ADI- 163  5.21E−08   4.755E−08 4.481 >10 15596 ADI- 164 4.17449E−10   NB   6.089E−09 NB 0.163 1.787 15597 ADI- 165  1.22E−10    1.23E−09   2.461E−10    6.52E−10 0.110 0.378 15599 ADI- 166 1.709E−09 1.62338E−10 1.41743E−09 1.47601E−10 1.309 0.958 15600 ADI- 167 3.21234E−10    2.0734E−10 3.28947E−10 1.93237E−10 0.046 0.084 15601 ADI- 168 7.62777E−10   NB 8.07428E−10 NB 0.046 0.015 15602 ADI- 169 3.76081E−09   NB  6.9735E−09   1.192E−08 0.795 0.273 15603 ADI- 170 4.302E−10 NB 4.60087E−10 1.76835E−09 0.081 0.082 15604 ADI- 171 1.38122E−09   1.62999E−10   3.487E−09  1.7094E−10 >10 >10 15605 ADI- 172 3.40832E−09   NB 5.75209E−09 5.88755E−09 >10 0.802 15606 ADI- 173 6.689E−08 NB NB NB >10 >10 15607 ADI- 174 5.21512E−10   NB 6.28141E−10 NB 0.022 >10 15609 ADI- 175 8.23723E−10   4.17101E−10 NB NB 0.727 >10 15610 ADI- 176 5.78704E−09    6.2637E−10 4.34028E−09 6.09385E−10 0.150 0.432 15611 ADI- 177 1.56006E−10     4.164E−10  1.5674E−10   3.528E−10 0.053 0.164 15612 ADI- 178 4.79157E−09   NB NB NB 0.862 3.038 15613 ADI- 179 4.09668E−10   NB 4.65658E−10 NB 0.027 0.059 15614 ADI- 180 6.02954E−10   NB   1.164E−08 NB 0.977 1.675 15615 ADI- 181 2.09622E−09   NB 1.73762E−09 NB 4.520 5.578 15616 ADI- 182 6.84697E−10   NB  7.1048E−10 NB 0.022 0.038 15617 ADI- 183 4.36681E−10   NB 5.35189E−10 NB 0.003 15618 ADI- 184 2.66134E−09     1.757E−09   6.913E−09   2.209E−09 1.453 0.377 15619 ADI- 185 2.702E−10 NB   1.404E−09 NB 0.077 0.053 15620 ADI- 186 5.97015E−10   NB 5.54785E−10 NB 0.018 0.021 15621 ADI- 187 1.39276E−09   NB 1.50943E−09 NB 0.544 1.367 15622 ADI- 188 3.8219E−10  NB 4.35256E−10 NB 0.054 0.108 15623 ADI- 189 3.91083E−10   NB 4.07332E−10 NB 0.051 0.033 15624 ADI- 190  2.73E−10 NB   2.614E−09 NB 0.239 1.198 15625 ADI- 191 3.33778E−09   5.46001E−10 3.38926E−09 6.53168E−10 14.180 >10 15626 ADI- 192 3.536E−09 1.57729E−10    1.61E−09 1.36519E−10 2.173 2.416 15627 ADI- 193 1.541E−10 2.46731E−09   6.595E−10 NB 0.014 0.034 15628 ADI- 194 3.4825E−10  2.28128E−10 3.59648E−10 2.13379E−10 0.085 0.088 15629 ADI- 195 5.67215E−09   NB NB NB >10 6.643 15630 ADI- 196 3.6846E−10  NB 5.52334E−10 NB 0.099 0.207 15631 ADI- 197 2.15308E−09     2.245E−09    2.94E−08 1.416 5.719 15632 ADI- 198 1.18343E−09   1.03681E−10 8.95656E−10 1.10865E−10 12.780 >10 15633 ADI- 199 5.974E−09 NB NB NB >10 >10 15634 ADI- 200 3.85951E−10   NB 4.31499E−10 NB 0.115 0.226 15635 ADI- 201 6.29327E−09   NB NB NB >10 6.444 15636 ADI- 202 3.51309E−09   NB 6.12933E−09 NB 0.357 1.053 15637 ADI- 203 3.69754E−10   NB 4.01606E−10 NB 0.178 >10 15638 ADI- 204 2.51604E−10   1.69348E−10 1.49365E−09 1.95886E−10 >10 4.819 15640 ADI- 205 1.2945E−10  1.60772E−10 1.35962E−10 1.36333E−10 0.184 0.483 15641 ADI- 206 1.281E−09 NB   2.813E−09 NB 0.499 0.005 15642 ADI- 207 1.5163E−10  NB 1.62338E−10 NB 0.039 0.115 15643 ADI- 208 NB 3.00616E−10 NB 1.94363E−10 >10 >10 15644 ADI- 209 8.7146E−09  3.67377E−10 4.60299E−09 3.52051E−10 >10 >10 15645 ADI- 210 3.758E−09 3.17561E−10 2.61712E−09   3.178E−09 0.846 >10 15646 ADI- 211 7.823E−09 NB NB NB >10 >10 15647 ADI- 212 3.9116E−10  NB 4.37541E−10 NB 0.064 0.145 15648 ADI- 213 3.19336E−10   NB 3.29327E−10 NB >10 2.195 15649 ADI- 214 1.671E−09 NB    3.52E−09 NB 8.297 0.016 15650 ADI- 215 1.72414E−09  2.29568E−10 2.08182E−09   4.531E−10 1.605 3.287 15651 ADI- 216  1.42E−10 4.98256E−09    3.77E−10 NB 0.012 0.036 15652 ADI- 217 NB 3.11769E−10 NB 3.89636E−10 >10 >10 15653 ADI- 218  5.49E−09 NB 4.47327E−09 NB 3.758 3.272 15654 ADI- 219 3.562E−08 NB   8.577E−09 NB >10 >10 15655 ADI- 220 3.27761E−09  NB 6.12933E−09 NB >10 0.021 15656 ADI- 221 5.65291E−09  NB NB NB >10 >10 15657 ADI- 222 3.35627E−09  1.79695E−10 1.80832E−09 1.69062E−10 6.250 >10 15658 ADI- 223 4.88759E−09    1.13E−09   1.105E−08   3.657E−09 >10 >10 15659 ADI- 224 1.06157E−09  9.80392E−11 8.90076E−10 1.04932E−10 17.340 >10 15660 ADI- 225 5.21105E−10   NB NB NB 0.021 >10 15661 ADI- 226 1.575E−08   3.086E−09 NB 6.250 >10 15662 ADI- 227 2.64166E−10    2.316E−09 2.86738E−10 NB 0.003 0.019 15663 ADI- 228 3.662E−09 NB NB NB >10 >10 15664 ADI- 229 8.253E−09 NB NB NB 12.720 6.250 15665 ADI- 230 NB 4.98504E−10 NB 5.46299E−10 1.407 >10 15666 ADI- 231 3.23415E−10  2.31134E−10 3.33278E−10 2.08442E−10 0.039 0.048 15667 *NN; non-neutralizing, NB; non-binding, ND; not determined. IgG KDs were calculated for antibodies with BLI binding responses > 0.1 nm. Antibodies with BLI binding responses < 0.05 nm were designated as NB.

TABLE 4 Bin, patch, and antigenic site assignments for anti-RSV antibodies Antibody Patch Antigenic number Assign- Site Name (Ab #) Bin Assignment ment Assignment ADI-15005 124 Site I Ab 8 I ADI-15006 125 Site I Ab ADI-15555 126 Mota ADI-15556 127 Mota 5, 6 III ADI-15557 128 High Affinity Ab. 1 IV ADI-15558 129 D25 2, 1 Ø ADI-15559 130 D25 2, 1 Ø ADI-15560 131 101F ADI-15561 132 Site I Ab ADI-15562 133 D25 2, 1 Ø ADI-15563 134 D25/mota/MPE8 4, 2 V ADI-15564 135 D25 1, 2 Ø ADI-15565 136 Unknown 2 UK ADI-15566 137 D25/mota/MPE8 2, 4 V ADI-15568 138 D25/mota 4, 2, 1 V ADI-15569 139 D25/mota/MPE8 4, 2 V ADI-15570 140 AM14 ADI-15571 141 High Affinity Ab. 1 ADI-15572 142 AM14 ADI-15573 143 Unknown ADI-15574 144 MPE8  2** III ADI-15575 145 Unknown ADI-15576 146 101F ADI-15577 147 High Affinity Ab. 2 ADI-15578 148 101F ADI-15579 149 Unknown ADI-15581 150 MPE8 ADI-15582 151 Mota/101F ADI-15583 152 High Affinity Ab. 1 8 IV ADI-15586 153 Unknown ADI-15587 154 Unknown 2, 1 Ø ADI-15588 155 Mota 5 II ADI-15589 156 Unknown ADI-15590 157 Mota ADI-15591 158 Mota/MPE8 2** III ADI-15592 159 Unknown ADI-15593 160 101F/Site I Ab ADI-15594 161 2, 1 Ø ADI-15595 162 D25 2, 1 Ø ADI-15596 163 101F ADI-15597 164 Mota/MPE8 2, 1* III ADI-15599 165 High Affinity Ab. 1 9 IV ADI-15600 166 101F 6, 8, 7 I ADI-15601 167 Mota 5 II ADI-15602 168 D25 2, 1 Ø ADI-15603 169 Mota ADI-15604 170 Mota/MPE8 2, 1** III ADI-15605 171 101F 6, 9 III ADI-15606 172 Mota ADI-15607 173 AM14 ADI-15609 174 D25/mota 4 V ADI-15610 175 Site I Ab I ADI-15611 176 Unknown ADI-15612 177 High Affinity Ab. 1 IV ADI-15613 178 AM14 ADI-15614 179 MPE8 III ADI-15615 180 Mota/MPE8 III ADI-15616 181 AM14 ADI-15617 182 D25 2, 1 Ø ADI-15618 183 D25 Ø ADI-15619 184 Unknown ADI-15620 185 High Affinity Ab. 1 9 IV ADI-15621 186 D25 1 Ø ADI-15622 187 MPE8 4 V ADI-15623 188 MPE8 III ADI-15624 189 Mota/MPE8 III ADI-15625 190 High Affinity Ab. 2 I ADI-15626 191 Unknown ADI-15627 192 101F ADI-15628 193 High Affinity Ab. 1 9 IV ADI-15629 194 Mota 5 II ADI-15630 195 AM14 ADI-15631 196 D25 4, 1 V ADI-15632 197 Mota/Site I Ab ADI-15633 198 101F IV ADI-15634 199 AM14 ADI-15635 200 Mota/MPE8 III ADI-15636 201 AM14 ADI-15637 202 101F ADI-15638 203 Mota/MPE8 III ADI-15640 204 High Affinity Ab. 2 I ADI-15641 205 High Affinity Ab. 1 9 IV ADI-15642 206 D25 1, 2 Ø ADI-15643 207 High Affinity Ab. 1 8 IV ADI-15644 208 MPE8/101F ADI-15645 209 Unknown ADI-15646 210 Site I Ab ADI-15647 211 Mota/MPE8 ADI-15648 212 Mota/MPE8 III ADI-15649 213 Mota/MPE8 III ADI-15650 214 D25 1, 2 Ø ADI-15651 215 Site I Ab 9 I ADI-15652 216 High Affinity Ab. 1 9 IV ADI-15653 217 101F ADI-15654 218 101F ADI-15655 219 Unknown ADI-15656 220 Unknown ADI-15657 221 MPE8 ADI-15658 222 Mota ADI-15659 223 Site I Ab ADI-15660 224 101F 9 IV ADI-15661 225 D25 4, 3, 1 V ADI-15662 226 Mota ADI-15663 227 Mota/MPE8 III ADI-15664 228 AM14 ADI-15665 229 Mota/MPE8 ADI-15666 230 MPE8/101F ADI-15667 231 Unknown 5 II **Two site III antibodies displayed weakly disrupted binding for patches 1 and/or 2. This disruption was much weaker than was what observed for D25 competitors.

TABLE 5 A subset of anti-RSV F antibodies cross-neutralize human metapneumovirus. Anti- HMPV- RSV- Prefusion Post- RSV F body A1 A2 RSV fusion Bind- number IC₅₀ IC₅₀ F K_(D) RSV F ing Name (Ab #) (μg/ml) (μg/ml) (M) K_(D) (M) Site ADI- 179 0.22 0.03 4.1 × 10⁻¹⁰ N.B. III  15614 ADI- 221 11.9 >25 5.7 × 10⁻⁹ N.B. III* 15657 ADI- 229 13.5 12.7 8.3 × 10⁻⁹ N.B. III* 15665 ADI- 211 20.3 >25 7.8 × 10⁻⁹ N.B. III* 15647 ADI- 188 0.37 0.05 2.1 × 10⁻⁹ N.B. III* 15623 MPE8 N/A 0.07 0.04 — — — Control N.B., non-binder; N/A, not applicable *Binding site assignment based on competition only.

Materials and Methods Study Design

To profile the antibody response to RSV F, peripheral blood mononuclear cells were obtained from an adult donor approximately between 20-35 years of age, and monoclonal antibodies from RSV F-reactive B cells were isolated therefrom. The antibodies were characterized by sequencing, binding, epitope mapping, and neutralization assays. All samples for this study were collected with informed consent of volunteers. This study was unblinded and not randomized. At least two independent experiments were performed for each assay.

Generation of RSV F Sorting Probes

The soluble prefusion and postfusion probes were based on the RSV F ΔFP and DS-Cav1 constructs that we previously crystallized and determined to be in the pre- and postfusion conformations, respectively (11, 15). To increase the avidity of the probes and to uniformly orient the RSV F proteins, the trimeric RSV F proteins were coupled to tetrameric streptavidin through biotinylation of a C-terminal AviTag. For each probe, both a C-terminal His-Avi tagged version and a C-terminal StrepTagII version were co-transfected into FreeStyle 293-F cells. The secreted proteins were purified first over Ni-NTA resin to remove trimers lacking the His-Avi tag. The elution from the Ni-NTA purification was then purified over Strep-Tactin resin. Due to the low avidity of a single StrepTagII for the Strep-Tactin resin, additional washing steps were able to remove singly StrepTagged trimers. This resulted in the purification of trimers containing two StrepTagII tagged monomers and therefore only one His-Avi tagged monomer. This purification scheme results in a single AviTag per trimer which greatly reduces the aggregation or ‘daisy-chaining’ that occurs when trimeric proteins containing three AviTags are incubated with tetrameric streptavidin. RSV F trimers were biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromatography on a Superdex 200 column (GE Healthcare). Quantification of the number of biotin moieties per RSV F trimer was performed using the Quant*Tag Biotin Kit per the manufacturer's instructions (Vector Laboratories).

Single B-Cell Sorting

Peripheral blood mononuclear cells were stained using anti-human IgG (BV605), IgA (FITC), CD27 (BV421), CD8 (PerCP-Cy5.5), CD14 (PerCP-Cy5.5), CD19 (PECy7), CD20 (PECy7) and a mixture of dual-labeled DS-Cav1 and F ΔFP tetramers (50 nM each). Dual-labeled RSV F tetramers were generated by incubating the individual AviTagged RSV F proteins with premium-grade phycoerythrin-labeled streptavidin (Molecular Probes) or premium-grade allophycocyanin-labeled streptavidin for at least 20 minutes on ice at a molar ratio of 4:1. Tetramers were prepared fresh for each experiment. Single cells were sorted on a BD fluorescence-activated cell sorter Aria II into 96-well PCR plates (BioRad) containing 20 μL/well of lysis buffer [5 μL of 5× first strand cDNA buffer (Invitrogen), 0.25 μL RNaseOUT (Invitrogen), 1.25 μL dithiothreitol (Invitrogen), 0.625 μL NP-40 (New England Biolabs), and 12.6 μL dH₂O]. Plates were immediately frozen on dry ice before storage at −80° C.

Amplification and Cloning of Antibody Variable Genes

Single B cell PCR was performed as described previously (22). Briefly, IgH, Igλ and Igκ variable genes were amplified by RT-PCR and nested PCR reactions using cocktails of IgG and IgA-specific primers (22). The primers used in the second round of PCR contained 40 base pairs of 5′ and 3′ homology to the cut expression vectors to allow for cloning by homologous recombination into Saccharomyces cerevisiae (40). PCR products were cloned into S. cerevisiae using the lithium acetate method for chemical transformation (41). Each transformation reaction contained 20 μL of unpurified heavy chain and light chain PCR product and 200 ng of cut heavy and light chain plasmids. Following transformation, individual yeast colonies were picked for sequencing and characterization.

Expression and Purification of IgGs and Fab Fragments

Anti-RSV F IgGs were expressed in S. cerevisiae cultures grown in 24-well plates, as described previously (23). Fab fragments used for competition assays were generated by digesting the IgGs with papain for 2 hours at 30° C. The digestion was terminated by the addition of iodoacetamide, and the Fab and Fc mixtures were passed over Protein A agarose to remove Fc fragments and undigested IgG. The flowthrough of the Protein A resin was then passed over CaptureSelect™ IgG-CH1 affinity resin (ThermoFischer Scientific), and eluted with 200 mM acetic acid/50 mM NaCl pH 3.5 into ⅛th volume 2M Hepes pH 8.0. Fab fragments then were buffer-exchanged into PBS pH 7.0.

Biolayer Interferometry Binding Analysis

IgG binding to DS-Cav1 and FΔ FP was determined by BLI measurements using a FortéBio Octet HTX instrument (Pall Life Sciences). For high-throughput K_(D) screening, IgGs were immobilized on AHQ sensors (Pall Life Sciences) and exposed to 100 nM antigen in PBS containing 0.1% BSA (PBSF) for an association step, followed by a dissociation step in PBSF buffer. Data was analyzed using the ForteBio Data Analysis Software 7. The data was fit to a 1:1 binding model to calculate an association and dissociation rate, and K_(D) was calculated using the ratio k_(d)/k_(a).

Antibody Competition Assays

Antibody competition assays were performed as previously described (23). Antibody competition was measured by the ability of a control anti-RSV F Fab to inhibit binding of yeast surface-expressed anti-RSV F IgGs to either DS-Cav1 or FΔ FP. 50 nM biotinylated DS-Cav1 or FΔ FP was pre-incubated with 1 μM competitor Fab for 30 min at room temperature and then added to a suspension of yeast expressing anti-RSV F IgG. Unbound antigen was removed by washing with PBS containing 0.1% BSA (PB SF). After washing, bound antigen was detected using streptavidin Alexa Fluor 633 at a 1:500 dilution (Life Technologies) and analyzed by flow cytometry using a FACSCanto II (BD Biosciences). The level of competition was assessed by measuring the fold reduction in antigen binding in the presence of competitor Fab relative to an antigen-only control. Antibodies were considered competitors when a greater than five-fold reduction was observed in the presence of control Fab relative to an antigen-only control.

Expression, Purification and Biotinylation of preF Patch Variants

A panel of 9 patches of 2-4 mutations uniformly covering the surface of the preF molecule was designed based on the structure of prefusion RSV F (10). For known antigenic sites, including those recognized by motavizumab, 101F, D25, AM14 and MPEG, patches incorporated residues associated with viral escape or known to be critical for antibody binding. Residues with high conservation across 184 subtype A, subtype B and bovine RSV F sequences were avoided where possible to minimize the likelihood of disrupting protein structure. The mutations present in each patch variant are shown in FIG. 7A. Mutations for each patch variant were cloned into the prefusion stabilized RSV F (DS-Cav1) construct with a C-terminal AviTag for site specific biotinylation. Proteins were secreted from FreeStyle 293-F cells, purified over Ni-NTA resin and biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromatography on a Superdex 200 column (GE Healthcare). A deglycosylated version of DS-Cav1 was produced by expressing DS-Cav1 in the presence of 1 μM kifunensine and digesting with 10% (wt/wt) EndoH before biotinylation.

Luminex Assay for Patch Variant Binding

Binding of isolated antibodies to the patch variants was determined using a high-throughput Luminex assay. Each biotinylated variant and a DS-Cav1 control were coupled to avidin coated MagPlex beads (Bio-Rad), each with a bead identification number reflecting a unique ratio of red and infrared dyes embedded within the bead. The coupled beads were then mixed with a six-fold serial dilution of each antibody, ranging from 400 nM to 1.4 pM, in a 384-well plate. Beads were washed using a magnetic microplate washer (BioTek) before incubation with a PE conjugated mouse anti-human IgG Fc secondary antibody (Southern Biotech). Beads were classified and binding of PE was measured using a FLEXMAP 3D flow cytometer (Luminex).

RSV Neutralization Assays

Viral stocks were prepared and maintained as previously described (61). Recombinant mKate-RSV expressing prototypic subtype A (strain A2) and subtype B (18537) F genes and the Katushka fluorescent protein were constructed as reported by Hotard et al. (62). HEp-2 cells were maintained in Eagle's minimal essential medium containing 10% fetal bovine serum supplemented with glutamine, penicillin and streptomycin. Antibody neutralization was measured by a fluorescence plate reader neutralization assay (15). A 30 μL solution of culture media containing 2.4×10⁴ HEp-2 cells was seeded in 384-well black optical bottom plate (Nunc, Thermo Scientific). IgG samples were serially diluted four-fold from 1:10 to 1:163840 and an equal volume of recombinant mKate-RSV A2 was added. Samples were mixed and incubated at 37° C. for one hour. After incubation, 50 μL mixture of sample and virus was added to cells in 384-well plate, and incubated at 37° C. for 22-24 hours. The assay plate was then measured for fluorescence intensity in a microplate reader at Ex 588 nm and Em 635 nm (SpectraMax Paradigm, molecular devices). IC₅₀ of neutralization for each sample was calculated by curve fitting using Prism (GraphPad Software Inc.).

Human Metapneuomovirus Neutralization Assays

Predetermined amounts of GFP-expressing hMPV recombinant virus (NL/1/00, A1 sublineage, a kind gift of Bernadette van den Hoogen and Ron Fouchier, Rotterdam, the Netherlands) were mixed with serial dilutions of monoclonal antibodies before being added to cultures of Vero-118 cells growing in 96-well plates with Dulbecco's Modified Eagle's medium supplemented with 10% fetal calf serum. Thirty-six hours later, the medium was removed, PBS was added and the amount of GFP per well was measured with a Tecan microplate reader M200. Fluorescence values were represented as percent of a virus control without antibody.

Polyreactivity Assay

Antibody polyreactivity was assessed using a previously described high-throughput assay that measures binding to solubilized CHO cell membrane preparations (SMPs) (43). Briefly, two million IgG-presenting yeast were transferred into a 96-well assay plate and pelleted to remove the supernatant. The pellet was resuspended in 50 μL of 1:10 diluted stock b-SMPs and incubated on ice for 20 minutes. Cells were then washed twice with ice-cold PBSF and the cell pellet was re-suspended in 50 μL of secondary labeling mix (Extravidin-R-PE, anti-human LCFITC, and propidium iodide). The mix was incubated on ice for 20 minutes followed by two washes with ice-cold PBSF. Cells were then re-suspended in 100 μL of ice-cold PB SF, and the plate was run on a FACSCanto II (BD Biosciences) using a HTS sample injector. Flow cytometry data was analyzed for mean fluorescence intensity in the R-PE channel and normalized to proper controls in order to assess non-specific binding.

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An informal sequence listing is provided in Table 6, below. The informal sequence listing for antibodies 124-231 provides the following sixteen (16) sequence elements contained in each of the 108 antibodies, identified as described above and designated as Antibody Numbers (Ab #) 124 through 231, in the following order:

-   -   Heavy chain variable region (“HC”) nucleic acid sequence     -   Heavy chain variable region (“HC”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) nucleic acid sequence     -   Heavy chain variable region CDR H2 (“H2”) amino acid sequence     -   Heavy chain variable region CDR H2 (“H2”) nucleic acid sequence     -   Heavy chain variable region CDR H3 (“H3”) amino acid sequence     -   Heavy chain variable region CDR H3 (“H3”) nucleic acid sequence     -   Light chain variable region(“LC”) nucleic acid sequence     -   Light chain variable region (“LC”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) nucleic acid sequence     -   Light chain variable region CDR L2 (“L2”) amino acid sequence     -   Light chain variable region CDR L2 (“L2”) nucleic acid sequence     -   Light chain variable region CDR L3 (“L3”) amino acid sequence     -   Light chain variable region CDR L3 (“L3”) nucleic acid sequence

The informal sequence listing for antibodies 232-244 provides the following ten (10) sequence elements contained in each of the 13 antibodies, identified as described above and designated as Antibody Numbers (Ab #) 232 through 244, in the following order:

-   -   Heavy chain variable region (“HC”) nucleic acid sequence     -   Heavy chain variable region (“HC”) amino acid sequence     -   Heavy chain variable region CDR H1 (“H1”) amino acid sequence     -   Heavy chain variable region CDR H2 (“H2”) amino acid sequence     -   Heavy chain variable region CDR H3 (“H3”) amino acid sequence     -   Light chain variable region(“LC”) nucleic acid sequence     -   Light chain variable region (“LC”) amino acid sequence     -   Light chain variable region CDR L1 (“L1”) amino acid sequence     -   Light chain variable region CDR L2 (“L2”) amino acid sequence     -   Light chain variable region CDR L3 (“L3”) amino acid sequence

TABLE 6 Informal Sequence Listing Anti- Seq. SEQ body Ref. ID No. No. NO. Sequence 124 1969    1 CAGGTGCAGCTGGTGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGA CCCTCACACTGACCTGCAGCTTCTCCGGGTTCTCACTCACCACTAGGAGA ATGTGTGTGAGCTGGATCCGTCAGACCCCAGGGAAGGCCCTGGAGTGGC TTGCACGCATTGATTGGGATGATGATAAAGACTACAGCACATCTCTGAA GACCAGGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTT ACAATGACCAACATGGACCCTGTGGACACGGCCACGTATTACTGTGCAC GGACCCACATTTATGATAGTAGTGGTTATTATCTATACTACTTTGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 124 1970    2 QVQLVESGPALVKPTQTLTLTCSFSGFSLTTRRMCVSWIRQTPGKALEWLA RIDWDDDKDYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTHI YDSSGYYLYYFDYWGQGTLVTVSS 124 1971    3 FSLTTRRMCVS 124 1972    4 TTCTCACTCACCACTAGGAGAATGTGTGTGAGC 124 1973    5 RIDWDDDKDYSTSLKT 124 1974    6 CGCATTGATTGGGATGATGATAAAGACTACAGCACATCTCTGAAGACC 124 1975    7 ARTHIYDSSGYYLYYFDY 124 1976    8 GCACGGACCCACATTTATGATAGTAGTGGTTATTATCTATACTACTTTGA CTAC 124 1977    9 GATATTGTGCTGACCCAGTCTCCATCCTCCCTGTCTGCATCTATAGGAGA CAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTGCCAGCTATTTA AATTGGTATCAGCAGAAACCAGGGAAAGCCCCTGAACTCCTGATCTATG CTGCAACCAATTTGCAGAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCGACCTGAAGATT TTGCAAGTTACTACTGTCAACAGAGTTACAGTAGTCCCTGGACGTTCGGC CAAGGGACCAAAGTGGATATCAAA 124 1978   10 DIVLTQSPSSLSASIGDRVTITCRASQTIASYLNWYQQKPGKAPELLIYAATN LQSGVPSRFSGSGSGTDFTLTISSLRPEDFASYYCQQSYSSPWTFGQGTKVDI K 124 1979   11 RASQTIASYLN 124 1980   12 CGGGCAAGTCAGACCATTGCCAGCTATTTAAAT 124 1981   13 AATNLQS 124 1982   14 GCTGCAACCAATTTGCAGAGT 124 1983   15 QQSYSSPWT 124 1984   16 CAACAGAGTTACAGTAGTCCCTGGACG 125 1985   17 GAGGTGCAGCTGGTGGAGTCTGGCCCAGGACTGGTGAAGCCTTCGGGGA CCCTGTCCCTCACCTGCACTGTCTCTGGTGACTCCATGAGTGATTACTAC TGGAGCTGGATCCGGCAGTCCCCAGGGAGGGGACTGGAGTGGCTTGGAT ATATCTATTACGATGGGAGCACCAACTACAACCCCTCCCTCAAGGGTCG AGGCACCATTTCAATAGACACGTCCAAGAGCCAGTTCTCCCTGACGCTG AGCTCTGTGAAGGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGGGA AGTACTATGATAGAGGTGGTTATTACCTGTTCTACCTTGACTACTGGGGC CAGGGAATACTGGTCACCGTCTCCTCA 125 1986   18 EVQLVESGPGLVKPSGTLSLTCTVSGDSMSDYYWSWIRQSPGRGLEWLGYI YYDGSTNYNPSLKGRGTISIDTSKSQFSLTLSSVKAADTAVYYCARGKYYD RGGYYLFYLDYWGQGILVTVSS 125 1987   19 DSMSDYYWS 125 1988   20 GACTCCATGAGTGATTACTACTGGAGC 125 1989   21 YIYYDGSTNYNPSLKG 125 1990   22 TATATCTATTACGATGGGAGCACCAACTACAACCCCTCCCTCAAGGGT 125 1991   23 ARGKYYDRGGYYLFYLDY 125 1992   24 GCGAGAGGGAAGTACTATGATAGAGGTGGTTATTACCTGTTCTACCTTG ACTAC 125 1993   25 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGA CAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTGCCAGCTATGTA AACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTTATCTATG CTGCATCCAGTTTGCAAGATGGGGTTCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGATTTCGCTCTCACCATCAGCAGTCTGCAACCTGAAGATT TTGCAATTTACTTTTGTCAACAGAGTTACAGTACCCCCATATTCACTTTC GGCCCTGGGACCAAGGTGGAAATCAAA 125 1994   26 DIRLTQSPSSLSASVGDRVTITCRASQTIASYVNWYQQKPGKAPKLLIYAASS LQDGVPSRFSGSGSGTDFALTISSLQPEDFAIYFCQQSYSTPIFTFGPGTKVEIK 125 1995   27 RASQTIASYVN 125 1996   28 CGGGCAAGTCAGACCATTGCCAGCTATGTAAAC 125 1997   29 AASSLQD 125 1998   30 GCTGCATCCAGTTTGCAAGAT 125 1999   31 QQSYSTPIFT 125 2000   32 CAACAGAGTTACAGTACCCCCATATTCACT 126 2001   33 GAGGTGCAGCTGGTGGAGTCTGGGGGCGCCTTGGTAAAGCCGGGGGGGT CCCTTAGACTCTCCTGTGTAGGCACTGGACTCACTTTCACTACTGCCTAC ATGAGCTGGGCCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGTC GTATTAAGAGCAAAAGTGATGGTGGGACAACAGACTACCCTACACCCGT CAAAGGCAGATTCACCATCTCAAGAGATGAATCCAAAAACACCCTGTAT CTGCAAATGAACAGCCTGAAAATCGAGGACACAGCCGTCTATTATTGTA CCACAGATAGGGGGATAACAGCTCGTCCTATCTTCGACTCCTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 126 2002   34 EVQLVESGGALVKPGGSLRLSCVGTGLTFTTAYMSWARQAPGKGLEWVGR IKSKSDGGTTDYPTPVKGRFTISRDESKNTLYLQMNSLKIEDTAVYYCTTDR GITARPIFDSWGQGTLVTVSS 126 2003   35 LTFTTAYMS 126 2004   36 CTCACTTTCACTACTGCCTACATGAGC 126 2005   37 RIKSKSDGGTTDYPTPVKG 126 2006   38 CGTATTAAGAGCAAAAGTGATGGTGGGACAACAGACTACCCTACACCCG TCAAAGGC 126 2007   39 TTDRGITARPIFDS 126 2008   40 ACCACAGATAGGGGGATAACAGCTCGTCCTATCTTCGACTCC 126 2009   41 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCTAGGGCGGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCGGGTTA TGATGTACATTGGTACAGGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATTTATGGTAACACCAAACGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTATGCCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGACGCTGATTATTACTGCCAGTCCTATGACGGCGGCCTGAGTGG TTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 126 2010   42 QSVLTQPPSVSGALGRRVTISCTGSSSNIGAGYDVHWYRQLPGTAPKLLIYG NTKRPSGVPDRFSGSKYATSASLAITGLQAEDDADYYCQSYDGGLSGYVFG TGTKLTVL 126 2011   43 TGSSSNIGAGYDVH 126 2012     44 ACTGGGAGCAGCTCCAACATCGGGGCGGGTTATGATGTACAT 126 2013   45 GNTKRPS 126 2014   46 GGTAACACCAAACGGCCCTCA 126 2015   47 QSYDGGLSGYV 126 2016   48 CAGTCCTATGACGGCGGCCTGAGTGGTTATGTC 127 2017   49 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCAACGTCAACATCTATGG AATCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA GGGATCATCCCTATTTATGATACAACAAAGTACGCACAGAAATTCCAGG ACAGAGTCACGATTACCGCGGACAAATCCACGAGTACAGCCTACATGGA GTTGAGCAGCCTGAGATCTGAGGACACGGCCGTATATTTCTGTGCGAGA GATCTTGATTACGATATTTTGACTGGTTATTCCGTAAACTACTACTACTA CGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 127 2018   50 QVQLVQSGAEVKKPGSSVKVSCKASGGNVNIYGISWVRQAPGQGLEWMG GIIPIYDTTKYAQKFQDRVTITADKSTSTAYMELSSLRSEDTAVYFCARDLD YDILTGYSVNYYYYGMDVWGQGTTVTVSS 127 2019   51 GNVNIYGIS 127 2020   52 GGCAACGTCAACATCTATGGAATCAGT 127 2021   53 GIIPIYDTTKYAQKFQD 127 2022   54 GGGATCATCCCTATTTATGATACAACAAAGTACGCACAGAAATTCCAGG AC 127 2023   55 ARDLDYDILTGYSVNYYYYGMDV 127 2024   56 GCGAGAGATCTTGATTACGATATTTTGACTGGTTATTCCGTAAACTACTA CTACTACGGTATGGACGTC 127 2025   57 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTGTGACAGCAGCCTAAGTGG TTGGGTGTTCGGCGGAGGGACCAAGCTGACCATCCTA 127 2026   58 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYG NINRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSCDSSLSGWVFGG GTKLTIL 127 2027   59 TGSSSNIGAGYDVH 127 2028   60 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 127 2029   61 GNINRPS 127 2030   62 GGTAACATCAATCGGCCCTCA 127 2031   63 QSCDSSLSGWV 127 2032   64 CAGTCCTGTGACAGCAGCCTAAGTGGTTGGGTG 128 2033   65 CAGGTCCAGCTTGTACAGTCTGGGGCTGAAGTGAAGAGGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTTTGCT ATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GGCTCATCCCTATCTTTGGTACACCAAACAACGCACAGAAGTTCCAGGG CAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAG CTGAGCAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTGCCTCATT ACGATATTTTGACTGGCAACCTGGGGGGTCCTACTGGTTCGACCCCTGGG GCCAGGGAACCCTGGTCACCGTCTCCTCA 128 2034   66 QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSFAINWVRQAPGQGLEWMGG LIPIFGTPNNAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCASLRYFD WQPGGSYWFDPWGQGTLVTVSS 128 2035   67 GTFSSFAIN 128 2036   68 GGCACCTTCAGCAGCTTTGCTATCAAC 128 2037   69 GLIPIFGTPNNAQKFQG 128 2038   70 GGGCTCATCCCTATCTTTGGTACACCAAACAACGCACAGAAGTTCCAGG GC 128 2039   71 ASLRYFDWQPGGSYWFDP 128 2040   72 GCCTCATTACGATATTTTGACTGGCAACCTGGGGGGTCCTACTGGTTCGA CCCC 128 2041   73 CAGCCTGGGCTGACTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAAGA CGGCCAGGATTGCCTGTGGGGGAGACAACATTGGAACTAAAGGAGTGC ACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCATCTATTA TGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGTTCCAACT CTGGGAACACGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATG AGGCCGACTACTACTGTCAGGTTTGGGATACTATTGATGATCATAAGGA TGGACTATTCGGCGGAGGGACCAAGCTCACCGTCCTA 128 2042   74 QPGLTQPPSVSVAPGKTARIACGGDNIGTKGVHWYQQKPGQAPVLVIYYDS DRPSGIPERFSGSNSGNTATLTISGVEAGDEADYYCQVWDTIDDHKDGLFGG GTKLTVL 128 2043   75 GGDNIGTKGVH 128 2044   76 GGGGGAGACAACATTGGAACTAAAGGAGTGCAC 128 2045   77 YDSDRPS 128 2046   78 TATGATAGCGACCGGCCCTCA 128 2047   79 QVWDTIDDHKDGL 128 2048   80 CAGGTTTGGGATACTATTGATGATCATAAGGATGGACTA 129 2049   81 CAGGTCCAGCTTGTGCAGTCTGGAGGTGAGGTGAAGAAGCCTGGCGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCACCTATGGA ATCAGCTGGGTGCGACAGGCCCCTGGACATGGGCTTGAGTGGCTGGGAT GGATCAGCCCTAAGAATGGCAACACAAAGTATGCACAGAAGGTCCAGG GCAGAGTCACCATGACCATAGACCCAACCACGAGTACAGCCTACATGGA ACTGAGGAGCCTGAGATCAGACGACACGGCCATGTATTACTGTGCGAGA GACTATATTGTAGCAATAGTGGCTGCTCTCCCCCACGGTATGGACGTCTG GGGCCAAGGGACCCTGGTCACTGTCTCCTCA 129 2050   82 QVQLVQSGGEVKKPGASVKVSCKASGYTFTTYGISWVRQAPGHGLEWLG WISPKNGNTKYAQKVQGRVTMTIDPTTSTAYMELRSLRSDDTAMYYCARD YIVAIVAALPHGMDVWGQGTLVTVSS 129 2051   83 YTFTTYGIS 129 2052   84 TACACCTTTACCACCTATGGAATCAGC 129 2053   85 WISPKNGNTKYAQKVQG 129 2054   86 TGGATCAGCCCTAAGAATGGCAACACAAAGTATGCACAGAAGGTCCAG GGC 129 2055   87 ARDYIVAIVAALPHGMDV 129 2056   88 GCGAGAGACTATATTGTAGCAATAGTGGCTGCTCTCCCCCACGGTATGG ACGTC 129 2057   89 CAGTCTGTCTTGACGCAGCCGCCCTCCCTGTCCGTGTCCCCAGGACAGAC AGCCAGCATCTCCTGCTCTGGGGATCAGTTGGGGAATAAATATGTTTGTT GGTATCAGCAGAAGCCAGGCCAGTCCCCTGTTCTGGTCATCTATCAAGA TTCCAGGCGGCCCTCAGGGGTCCCTGAGCGATTCTCTGGCTCCAACTCCG GGAACACAGCCACTCTGACCGTCGGCGGGACCCAGCCTATGGATGAGGC TGACTATTACTGTCAGGCGTGGGACAGCAGCATTCGGGTATTCGGCGGA GGGACCAAGGTGACCGTCCTA 129 2058   90 QSVLTQPPSLSVSPGQTASISCSGDQLGNKYVCWYQQKPGQSPVLVIYQDSR RPSGVPERFSGSNSGNTATLTVGGTQPMDEADYYCQAWDSSIRVFGGGTKV TVL 129 2059   91 SGDQLGNKYVC 129 2060   92 TCTGGGGATCAGTTGGGGAATAAATATGTTTGT 129 2061   93 QDSRRPS 129 2062   94 CAAGATTCCAGGCGGCCCTCA 129 2063   95 QAWDSSIRV 129 2064   96 CAGGCGTGGGACAGCAGCATTCGGGTA 130 2065   97 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCTCCTTGAGCACCTATGG GATCCACTGGGTGCGACAGGCCCCTGGCCAAGGCCTTGAGTGGGTGGGA GGGGTCATGACTGTCTATGGCAAAACAACCTACGGACAGAACTTCCAGG GCAGAGTCACCATTGCCGTGGACAGATCGACCAACACAGCCTACATGGA ACTGAGCAGCCTAACATCTGACGACACGGGTACTTATTACTGTGCGACA GACTCCTACTATGTTTGGACTGGTTCTTATCCCCCCCCCTTTGACCTCTGG GGCCAGGGAACCCTGGTCACCGTCTCCTCA 130 2066   98 QVQLVQSGAEVKKPGSSVKVSCKASGGSLSTYGIHWVRQAPGQGLEWVGG VMTVYGKTTYGQNFQGRVTIAVDRSTNTAYMELSSLTSDDTGTYYCATDS YYVWTGSYPPPFDLWGQGTLVTVSS 130 2067   99 GSLSTYGIH 130 2068  100 GGCTCCTTGAGCACCTATGGGATCCAC 130 2069  101 GVMTVYGKTTYGQNFQG 130 2070  102 GGGGTCATGACTGTCTATGGCAAAACAACCTACGGACAGAACTTCCAGG GC 130 2071  103 ATDSYYVWTGSYPPPFDL 130 2072  104 GCGACAGACTCCTACTATGTTTGGACTGGTTCTTATCCCCCCCCCTTTGA CCTC 130 2073  105 GAAATTGTGTTGACCCAGACTCCAGGCACCCAGTCTTTGTCTCCAGGGCA AAGTGCCACCCTCTCCTGCAGGGCCAGTCACAGTGTCGGCAACGACTAC TTGGCCTGGTATCAGCAGAAGCCTGGCCAGTCTCCCCGGCTCCTCATTCA CGGTGCATACAGGAGGGACTCTGGCATCCCAGACAGGTTCATTGGCAGT GGGTCTGGGACAGACTTCACTCTCACCATCGACAGTCTGGAGCCTGACG ATTGTGCAGTATATTACTGTCAGCAGTATGGGAGCTGGCCTCTCACTTTC GGCGGAGGGACCAAAGTGGATATCAAA 130 2074  106 EIVLTQTPGTQSLSPGQSATLSCRASHSVGNDYLAWYQQKPGQSPRLLIHGA YRRDSGIPDRFIGSGSGTDFTLTIDSLEPDDCAVYYCQQYGSWPLTFGGGTK VDIK 130 2075  107 RASHSVGNDYLA 130 2076  108 AGGGCCAGTCACAGTGTCGGCAACGACTACTTGGCC 130 2077  109 GAYRRDS 130 2078  110 GGTGCATACAGGAGGGACTCT 130 2079  111 QQYGSWPLT 130 2080  112 CAGCAGTATGGGAGCTGGCCTCTCACT 131 2081  113 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGTTACCTCTGGATTCATCTTCAGCAATTATGCT ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG TTATATCCTTTGATGCAGACAATGAATATTATGCAGAGTCCGTGAAGGG CCGATTCACCATCTCCAGAGACAATTCCAAGAACACGATGTATCTGCAA ATGAACAGCCTGAGAGCCGGGGACACAGCTCTCTATTACTGTGCGAGAG ATCCTCTGGGTATAGGAGTGAAGGGCTACGTTGACTTCTGGGGCCAGGG AACCCTGGTCACCGTCTCCTCA 131 2082  114 EVQLVESGGGVVQPGRSLRLSCVTSGFIFSNYAMHWVRQAPGKGLEWVAV ISFDADNEYYAESVKGRFTISRDNSKNTMYLQMNSLRAGDTALYYCARDPL GIGVKGYVDFWGQGTLVTVSS 131 2083  115 FIFSNYAMH 131 2084  116 TTCATCTTCAGCAATTATGCTATGCAC 131 2085  117 VISFDADNEYYAESVKG 131 2086  118 GTTATATCCTTTGATGCAGACAATGAATATTATGCAGAGTCCGTGAAGG GC 131 2087  119 ARDPLGIGVKGYVDF 131 2088  120 GCGAGAGATCCTCTGGGTATAGGAGTGAAGGGCTACGTTGACTTC 131 2089  121 TCCTCTGAGCTGAGTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAGAGA CGGCCAGGATTACTTGTGGGGGAGACAACTTTGGAAGTGACGGTCTGCA CTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGTTGGTCATCTATTAT GATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCCGGCTCCATCTC TGGGAACACGGCCACCTTGACCATCAGCAGGGTCGAAGCCGGGGATGA GGCCGACTATTTCTGTCAGGTGTGGGATAGTATTAGTGATCATCTGGTAT TCGGCGGGGGGACCAAGGTGACCGTCCTA 131 2090  122 SSELSQPPSVSVAPGETARITCGGDNFGSDGLHWYQQKPGQAPVLVIYYDSD RPSGIPERFSGSISGNTATLTISRVEAGDEADYFCQVWDSISDHLVFGGGTKV TVL 131 2091  123 GGDNFGSDGLH 131 2092  124 GGGGGAGACAACTTTGGAAGTGACGGTCTGCAC 131 2093  125 YDSDRPS 131 2094  126 TATGATAGCGACCGGCCCTCA 131 2095  127 QVWDSISDHLV 131 2096  128 CAGGTGTGGGATAGTATTAGTGATCATCTGGTA 132 2097  129 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGTTATGCT ATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GGATCATCCCTGCCTTTGGTACAACAATCTACGCACAGAGGTTCCAGGA CAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAG CTGAGGAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGGT CACCACCCTTTTGGAGTGACTATAGCCGTGGGTGGTTCGACCCCTGGGGC CAGGGAACCCTGGTCACCGTCTCCTCA 132 2098  130 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAINWVRQAPGQGLEWMG GIIPAFGTTIYAQRFQDRVTITADKSTSTAYMELRSLRSEDTAVYYCARSPPF WSDYSRGWFDPWGQGTLVTVSS 132 2099  131 GTFSSYAIN 132 2100  132 GGCACCTTCAGCAGTTATGCTATCAAC 132 2101  133 GIIPAFGTTIYAQRFQD 132 2102  134 GGGATCATCCCTGCCTTTGGTACAACAATCTACGCACAGAGGTTCCAGG AC 132 2103  135 ARSPPFWSDYSRGWFDP 132 2104  136 GCGAGGTCACCACCCTTTTGGAGTGACTATAGCCGTGGGTGGTTCGACC CC 132 2105  137 GAAACGACACTCACGCAGTCTCCATCCGCCCTGTCTGCATCTGTAGGAG ACAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTAGCGGCTATTT AAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTAT GCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCGAGATTCAGTGGCAGTA GCGCTGGGACAGATTTCACTCTCTCCATCAGCAATCTACAACCTGAAGAT TTTGCAACTTACTACTGTCAACAGAGTTACACTACCCCGTGGACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA 132 2106  138 ETTLTQSPSALSASVGDRVTITCRASQTISGYLNWYQQKPGKAPKLLIYAAS SLQSGVPSRFSGSSAGTDFTLSISNLQPEDFATYYCQQSYTTPWTFGQGTKV EIK 132 2107  139 RASQTISGYLN 132 2108  140 CGGGCAAGTCAGACCATTAGCGGCTATTTAAAT 132 2109  141 AASSLQS 132 2110  142 GCTGCATCCAGTTTGCAAAGT 132 2111  143 QQSYTTPWT 132 2112  144 CAACAGAGTTACACTACCCCGTGGACG 133 2113  145 CAGGTCCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGAGAC TCTCTGAAGATCTCCTGTAAGAATGCTGGACACACCTCTAGAATCTACTG GATCGCCTGGGTGCGCCAGATGCCCGCGAAAGGCCTGGAGTACATGGGC ATCATCTTTCCTGGTGACTCTGATACCAGATACAGTCCGTCCTTCCGAGG CCAGGTCACCATCTCAGCCGACAGGTCCATCAGAACTGCCTACCTGCAG TTGAGCAGCCTGAAGGCCTCGGACACCGGCATTTATTACTGTGCGACAC AGGGGCTTGAGGGGGCTTTTGACTACTGGGGCCAGGGAACCCTGGTCAC CGTCTCCTCA 133 2114  146 QVQLVQSGAEVKKPGDSLKISCKNAGHTSRIYWIAWVRQMPAKGLEYMGII FPGDSDTRYSPSFRGQVTISADRSIRTAYLQLSSLKASDTGIYYCATQGLEGA FDYWGQGTLVTVSS 133 2115  147 HTSRIYWIA 133 2116  148 CACACCTCTAGAATCTACTGGATCGCC 133 2117  149 IIFPGDSDTRYSPSFRG 133 2118  150 ATCATCTTTCCTGGTGACTCTGATACCAGATACAGTCCGTCCTTCCGAGG C 133 2119  151 ATQGLEGAFDY 133 2120  152 GCGACACAGGGGCTTGAGGGGGCTTTTGACTAC 133 2121  153 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACCAGTTA AATTGGTATCAGCAGAAACCAGGGACAGCCCCTAAGCTCCTCATCTACG ATGCATCCTTTTTGCAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGG ATCTGGGACACATTTTACTTTCACCATCACCAGCCTGCAGCCTGAAGATT TTGCAACATATTTCTGTCAGCATTATGATAGTTTCCCCATATTCACTTTCG GCCCTGGGACCAAGCTGGAGATCAAA 133 2122  154 DIRLTQSPSSLSASVGDRVTITCQASQDISNQLNWYQQKPGTAPKLLIYDASF LQTGVPSRFSGSGSGTHFTFTITSLQPEDFATYFCQHYDSFPIFTFGPGTKLEI K 133 2123  155 QASQDISNQLN 133 2124  156 CAGGCGAGTCAGGACATTAGCAACCAGTTAAAT 133 2125  157 DASFLQT 133 2126  158 GATGCATCCTTTTTGCAAACA 133 2127  159 QHYDSFPIFT 133 2128  160 CAGCATTATGATAGTTTCCCCATATTCACT 134 2129  161 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGT CCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCC ATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAG GCATCAGTTGGAATAGTGGTATTGTAAAGTATGCGGACTCTGTGAAGGG CCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAA ATGAACAGTCTGAGAACTGAGGACACGGCCTTGTATTATTGTGTAAAAG ACGGTTATACCAGCAGTTGGCACTCGGACTACCACTACGGCTTGGACGT CTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 134 2130  162 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVS GISWNSGIVKYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCVKDG YTSSWHSDYHYGLDVWGQGTTVTVSS 134 2131  163 FTFDDYAMH 134 2132  164 TTCACCTTTGATGATTATGCCATGCAC 134 2133  165 GISWNSGIVKYADSVKG 134 2134  166 GGCATCAGTTGGAATAGTGGTATTGTAAAGTATGCGGACTCTGTGAAGG GC 134 2135  167 VKDGYTSSWHSDYHYGLDV 134 2136  168 GTAAAAGACGGTTATACCAGCAGTTGGCACTCGGACTACCACTACGGCT TGGACGTC 134 2137  169 GATATTGTGATGACTCAGTCTCCAGCCACCCTGTCTCTGTCTCCAGGGGA CAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAATGTTATCAGCAACTTG GCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATA CTGTATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATT TTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCTCTCACTTTCGGC GGAGGGACCAAGGTGGAAATCAAA 134 2138  170 DIVMTQSPATLSLSPGDRATLSCRASQNVISNLAWYQQKPGQAPRLLIYTVS TRATGIPARFSGSGSGTDFTLTISSLQSEDFAVYYCQQYNNWPLTFGGGTKV EIK 134 2139  171 RASQNVISNLA 134 2140  172 AGGGCCAGTCAGAATGTTATCAGCAACTTGGCC 134 2141  173 TVSTRAT 134 2142  174 ACTGTATCCACCAGGGCCACT 134 2143  175 QQYNNWPLT 134 2144  176 CAGCAGTATAATAACTGGCCTCTCACT 135 2145  177 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCGT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGACACCTTCAACAGTTATTCC ATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GAATCCTCCCTATGTTTGGTTCGTCAGACTACGCACAGAAGTTCCAGGGC AGACTCACAATTACCGCGGACGAATCCACGAGGACAGCCTACATGGAGC TGAACAGTCTGACATCTGAGGACACGGCCATTTACTACTGTGCGAGAGA CAATTACTATGTTTGGACTGGTCGTTATCCCGAATTTGACTTCTGGGGCC AGGGAACCCTGGTCACCGTCTCCTCA 135 2146  178 QVQLVQSGAEVKKPGSSVKVSCKASGDTFNSYSISWVRQAPGQGLEWMGG ILPMFGSSDYAQKFQGRLTITADESTRTAYMELNSLTSEDTAIYYCARDNYY VWTGRYPEFDFWGQGTLVTVSS 135 2147  179 DTFNSYSIS 135 2148  180 GACACCTTCAACAGTTATTCCATCAGC 135 2149  181 GILPMFGSSDYAQKFQG 135 2150  182 GGAATCCTCCCTATGTTTGGTTCGTCAGACTACGCACAGAAGTTCCAGGG C 135 2151  183 ARDNYYVWTGRYPEFDF 135 2152  184 GCGAGAGACAATTACTATGTTTGGACTGGTCGTTATCCCGAATTTGACTT C 135 2153  185 GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCCTTGTCTCCAGGGGA TGAAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCAGCAATTAC TTAGCCTGGTACCAGCAGAGGCCTGGCCAGGCTCCCAGGCTCCTCATCTC TGGTGCATCCAGAAGGGCCACTGCCGTCCCAGACAGGTTCAGTGGCAGT GGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAG ATTTTGCAGTTTATTACTGTCAGCAATATGGAAGCACACCGATCACCTTC GGCCAGGGGACACGACTGGAGATTAAA 135 2154  186 EIVLTQSPGTLSLSPGDEATLSCRASQSVTSNYLAWYQQRPGQAPRLLISGAS RRATAVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSTPITFGQGTRLE IK 135 2155  187 RASQSVTSNYLA 135 2156  188 AGGGCCAGTCAGAGTGTTACCAGCAATTACTTAGCC 135 2157  189 GASRRAT 135 2158  190 GGTGCATCCAGAAGGGCCACT 135 2159  191 QQYGSTPIT 135 2160  192 CAGCAATATGGAAGCACACCGATCACC 136 2161  193 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACTTTCACCAATGATATA AACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGGTGG ATGAACCCTAACAATGGTCACACAGGCTATGCACAGAGCTTCGAGGGCA GAGTCAGCATGACCAGGAACTCCGCCATAAACACAGCCTACCTGGAGCT GAGCAGCCTGAGATTTGACGATACGGCCATATATTATTGTGTATACAATT TCTGGAGTGATTCTTCAGTCTCCTGGGGCCAGGGAACCCTGGTCACCGTC TCCTCA 136 2162  194 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNDINWVRQATGQGLEWMGW MNPNNGHTGYAQSFEGRVSMTRNSAINTAYLELSSLRFDDTAIYYCVYNFW SDSSVSWGQGTLVTVSS 136 2163  195 YTFTNDIN 136 2164  196 TACACTTTCACCAATGATATAAAC 136 2165  197 WMNPNNGHTGYAQSFEG 136 2166  198 TGGATGAACCCTAACAATGGTCACACAGGCTATGCACAGAGCTTCGAGG GC 136 2167  199 VYNFWSDSSVS 136 2168  200 GTATACAATTTCTGGAGTGATTCTTCAGTCTCC 136 2169  201 CAGTCTGTCGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GTGTCGCCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGCCAGGTTA TGATGTACACTGGTATCAGCAACTTCCGGGAGCAGCCCCCAAACTCCTC ATCTATGGTGACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTAC CTCCAAGTCTGGCACCTCAGTTTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTCCGTGG TTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 136 2170  202 QSVVTQPPSVSGAPGQSVAISCTGSSSNIGPGYDVHWYQQLPGAAPKLLIYG DSNRPSGVPDRFSTSKSGTSVSLAITGLQAEDEADYYCQSYDSSLRGYVFGT GTKLTVL 136 2171  203 TGSSSNIGPGYDVH 136 2172  204 ACTGGGAGCAGCTCCAACATCGGGCCAGGTTATGATGTACAC 136 2173  205 GDSNRPS 136 2174  206 GGTGACAGCAATCGGCCCTCA 136 2175  207 QSYDSSLRGYV 136 2176  208 CAGTCCTATGACAGCAGCCTCCGTGGTTATGTC 137 2177  209 CAGGTCCAGCTTGTACAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGTTTCACCTTTACTAATTATGGT ATAAGTTGGGTGCGACAGGCCCCTGGACGAGGGCTTGAGTGGATGGGCT GGATCAGCGCTTACAATGGTAACACAGAGTATGCACAGAAGCTCCAAGA CAGACTCACCATGACCACAGACACATCTACGAACACAGCCTACATGGAG TTGAGGAGCCTGAGATCTGACGACACGGCCCTATATTATTGTGCGAGAG AGTCAGGTGTCGCAGCAGCTGCTACCTTACTTTACTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCA 137 2178  210 QVQLVQSGAEVKKPGASVKVSCKASGFTFTNYGISWVRQAPGRGLEWMG WISAYNGNTEYAQKLQDRLTMTTDTSTNTAYMELRSLRSDDTALYYCARE SGVAAAATLLYWGQGTLVTVSS 137 2179  211 FTFTNYGIS 137 2180  212 TTCACCTTTACTAATTATGGTATAAGT 137 2181  213 WISAYNGNTEYAQKLQD 137 2182  214 TGGATCAGCGCTTACAATGGTAACACAGAGTATGCACAGAAGCTCCAAG AC 137 2183  215 ARESGVAAAATLLY 137 2184  216 GCGAGAGAGTCAGGTGTCGCAGCAGCTGCTACCTTACTTTAC 137 2185  217 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACA ACCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGCGATG GAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAG GCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGA TTCAGCGGCAGTGGGTCAGGCGCTGATTTCACACTGAAAATCAGCAGGG TGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTATATACTG GCCTCGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA 137 2186  218 ETTLTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLSWFQQRPGQSPRRLI YKVSNRDSGVPDRFSGSGSGADFTLKISRVEAEDVGVYYCMQGIYWPRTFG QGTKVDIK 137 2187  219 RSSQSLVYSDGNTYLS 137 2188  220 AGGTCTAGTCAAAGCCTCGTATACAGCGATGGAAACACCTACTTGAGT 137 2189  221 KVSNRDS 137 2190  222 AAGGTTTCTAACCGGGACTCT 137 2191  223 MQGIYWPRT 137 2192  224 ATGCAAGGTATATACTGGCCTCGGACG 138 2193  225 CAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGCAGAAGCCTGGGGCCT CAGTGAAGATTTCTTGCAAGGCATCTGGATACAAGTTCATCAGCTACTCC ATACACTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGAG TAATCAACCCTGGTGGCGGTCTCACAAACTATGCACAGAAGTTCCAGGA CAGACTCACCATGACCAGGGACACGTCCACGGCCACAGTGACCATGGAA CTGAGGAGCCTGAGATCTGACGACAGGGCCGTATATTTTTGTGGTAGAG AAGACTCATATTGTAGTGGAGACAGCTGCTTCAATTCCGGTTCGGGGCG CTGGGTCGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 138 2194  226 QVQLVESGAEVQKPGASVKISCKASGYKFISYSIHWVRQAPGQGLEWMGVI NPGGGLTNYAQKFQDRLTMTRDTSTATVTMELRSLRSDDRAVYFCGREDS YCSGDSCFNSGSGRWVDSWGQGTLVTVSS 138 2195  227 YKFISYSIH 138 2196  228 TACAAGTTCATCAGCTACTCCATACAC 138 2197  229 VINPGGGLTNYAQKFQD 138 2198  230 GTAATCAACCCTGGTGGCGGTCTCACAAACTATGCACAGAAGTTCCAGG AC 138 2199  231 GREDSYCSGDSCFNSGSGRWVDS 138 2200  232 GGTAGAGAAGACTCATATTGTAGTGGAGACAGCTGCTTCAATTCCGGTT CGGGGCGCTGGGTCGACTCC 138 2201  233 GACATCCAGGTGACCCAGTCTCCATCGTCCCTGTCTGCATCTGTCGGAGA CAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCGTTATCACCTATTTA AATTGGTATCAGCAGAAACCAGGGAAAGCCCCTCAACTCCTGGTCTATG CTGCTTCCATTTTGCAAAGTGGGGTCCCATCCAGCTTCAGTGGCAGTGGA TCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTT TGCAACTTACTACTGTCAACAGACTTACAGTACCCCTCATACTTTTGGCC AGGGGACCAAAGTGGATATCAAA 138 2202  234 DIQVTQSPSSLSASVGDRVTITCRASQSVITYLNWYQQKPGKAPQLLVYAAS ILQSGVPSSFSGSGSGTDFTLTISSLQPEDFATYYCQQTYSTPHTFGQGTKVDI K 138 2203  235 RASQSVITYLN 138 2204  236 CGGGCAAGTCAGAGCGTTATCACCTATTTAAAT 138 2205  237 AASILQS 138 2206  238 GCTGCTTCCATTTTGCAAAGT 138 2207  239 QQTYSTPHT 138 2208  240 CAACAGACTTACAGTACCCCTCATACT 139 2209  241 GAGGTGCAGCTGGTGGAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTGCCAACTATGGT ATCACCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTACATGGGAT GGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCAGGG CAGAGTCACCATGACCACGGACACATCCACGAGCACAGCGTACATGGAG CTGAGGAGCCTGAGATCTGACGACACGGCCATTTATTACTGTGCGAGAG ATCCCGGTGTTACGGCTGCTGTGCTACTTGACTACTGGGGCCAGGGAGC CCTGGTCACCGTCTCCTCA 139 2210  242 EVQLVESGAEVKKPGASVKVSCKASGYTFANYGITWVRQAPGQGLEYMG WISAYNGNTNYAQKFQGRVTMTTDTSTSTAYMELRSLRSDDTAIYYCARDP GVTAAVLLDYWGQGALVTVSS 139 2211  243 YTFANYGIT 139 2212  244 TACACCTTTGCCAACTATGGTATCACC 139 2213  245 WISAYNGNTNYAQKFQG 139 2214  246 TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCAGG GC 139 2215  247 ARDPGVTAAVLLDY 139 2216  248 GCGAGAGATCCCGGTGTTACGGCTGCTGTGCTACTTGACTAC 139 2217  249 GATATTGTGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACA GCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATTCAGTGATG GAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAG GCGCCTACTTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGAT TCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGACAATCAGCAGGGT GGAGGCTGAGGATGTTGGGGTTTATTACTGCTTGCAAGGTACACCCCCTT ACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 139 2218  250 DIVLTQSPLSLPVTLGQPASISCRSSQSLVFSDGNTYLSWFQQRPGQSPRRLL YKVSNRDSGVPDRFSGSGSGTDFTLTISRVEAEDVGVYYCLQGTPPYTFGQG TKVDIK 139 2219  251 RSSQSLVFSDGNTYLS 139 2220  252 AGGTCTAGTCAAAGCCTCGTATTCAGTGATGGAAACACCTACTTGAGT 139 2221  253 KVSNRDS 139 2222  254 AAGGTTTCTAACCGGGACTCT 139 2223  255 LQGTPPYT 139 2224  256 TTGCAAGGTACACCCCCTTACACT 140 2225  257 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAAGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATCCT ATGCACTGGGTCCGCCAGGCTCCAGGCGCGGGGCTGGAGTGGATGGCCG TAATCTCATATGATGGAGCCAATAAATACTATGAAGACTCCTTAAAGGG CCGATTCACCATCTCCAGAGACAATTCCAAGGACACTCTGTTTCTGCAAA TGAACAACCTGAGACCTGAGGACACGGCTGTCTATTACTGTGCGAGAGG GAGGACTTCGCATATAAATACACCCGAGACTAAGTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA 140 2226  258 QVQLVESGGGVVQPGKSLRLSCAASGFTFSSYPMHWVRQAPGAGLEWMA VISYDGANKYYEDSLKGRFTISRDNSKDTLFLQMNNLRPEDTAVYYCARGR TSHINTPETKWGQGTLVTVSS 140 2227  259 FTFSSYPMH 140 2228  260 TTCACCTTCAGTAGCTATCCTATGCAC 140 2229  261 VISYDGANKYYEDSLKG 140 2230  262 GTAATCTCATATGATGGAGCCAATAAATACTATGAAGACTCCTTAAAGG GC 140 2231  263 ARGRTSHINTPETK 140 2232  264 GCGAGAGGGAGGACTTCGCATATAAATACACCCGAGACTAAG 140 2233  265 GAAATTGTGTTGACGCAGTCTCCAACCTTAGTGTCTGCATCTACAGGAGA CACAGTCACCATCAGTTGCCGGATGAGTCAGGGCATTAACGGTTATTTA GCCTGGTTTCAGAAAAAACCAGGGAAAGCCCCTGACCTCCTGATCTATG GTGCATCCACTTTGCAAGATGGGGTCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCAGTCGCCTGCAGTCTGAAGATT TGGCAACTTATTATTGTCAACAGTATTACAGTTTGCCGTGGACGTTCGGC CAAGGGACCAAAGTGGATATCAAA 140 2234  266 EIVLTQSPTLVSASTGDTVTISCRMSQGINGYLAWFQKKPGKAPDLLIYGAS TLQDGVPSRFSGSGSGTDFTLTISRLQSEDLATYYCQQYYSLPWTFGQGTKV DIK 140 2235  267 RMSQGINGYLA 140 2236  268 CGGATGAGTCAGGGCATTAACGGTTATTTAGCC 140 2237  269 GASTLQD 140 2238  270 GGTGCATCCACTTTGCAAGAT 140 2239  271 QQYYSLPWT 140 2240  272 CAACAGTATTACAGTTTGCCGTGGACG 141 2241  273 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGATACAGCTTCACCGACTACTAT ATACACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATAGGAT GGATCAACCCTAACAGTGGTGGCACAACCTTTGCACAGAACTTTCAGGG CAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTTCCTGGAG CTGAGCAGGCTAAAATCTGACGACACGGCCGTATATTATTGTGCGAGAG ACGTTCTCTGGTTAAACGGATTCTGGGGCCTGGGAACCCTGGTCACCGTC TCTTCA 141 2242  274 QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYIHWVRQAPGQGLEWIG WINPNSGGTTFAQNFQGRVTMTRDTSISTAFLELSRLKSDDTAVYYCARDV LWLNGFWGLGTLVTVSS 141 2243  275 YSFTDYYIH 141 2244  276 TACAGCTTCACCGACTACTATATACAC 141 2245  277 WINPNSGGTTFAQNFQG 141 2246  278 TGGATCAACCCTAACAGTGGTGGCACAACCTTTGCACAGAACTTTCAGG GC 141 2247  279 ARDVLWLNGF 141 2248  280 GCGAGAGACGTTCTCTGGTTAAACGGATTC 141 2249  281 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGA AGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTAT GTATCCTGGTATCAGCAGTTCCGAGGAACAGCCCCCAAAGTCCTCATTTA TGAAAATAATAAGCGAACCTCAGGGATTCCTGACCGATTCTCTGGCTCC AAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGG ACGAGGCCGATTATTACTGCGGAACATGGGATAGCAGCCTGAGTACTGG CCCCTATGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA 141 2250  282 QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQFRGTAPKVLIYEN NKRTSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSTGPYVVF GGGTKLTVL 141 2251  283 SGSSSNIGNNYVS 141 2252  284 TCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCC 141 2253  285 ENNKRTS 141 2254  286 GAAAATAATAAGCGAACCTCA 141 2255  287 GTWDSSLSTGPYVV 141 2256  288 GGAACATGGGATAGCAGCCTGAGTACTGGCCCCTATGTGGTA 142 2257  289 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGCGAAGAAGCCTGGGGCCT CAGTGAAGGTTTCCTGTAAGGCATCTGGATATACCTTTACCAGCTACTAT TTGCACTGGGTGCGACAGGCCCCTGGACAAGGGCCTGAGTGGATGGGAA TAATCAACCCTGGTGGTGGTAGCACAGAGTTGTCACAGAAGTTCCAGGG CAGAGTCACCTTGACTAGGGACACGTCCACGAGCACAGTCTACATGGAG GTGACCAGCCTGACATCTGAGGACACGGCCGTCTATTACTGTGCGAGAG CCCGGATACAGCTCTGGGCACCAAATTACTACGGTATGGACGTCTGGGG CCAAGGGACCACGGTCACCGTCTCTTCA 142 2258  290 QVQLVQSGAEAKKPGASVKVSCKASGYTFTSYYLHWVRQAPGQGPEWMG IINPGGGSTELSQKFQGRVTLTRDTSTSTVYMEVTSLTSEDTAVYYCARARI QLWAPNYYGMDVWGQGTTVTVSS 142 2259  291 YTFTSYYLH 142 2260  292 TATACCTTTACCAGCTACTATTTGCAC 142 2261  293 IINPGGGSTELSQKFQG 142 2262  294 ATAATCAACCCTGGTGGTGGTAGCACAGAGTTGTCACAGAAGTTCCAGG GC 142 2263  295 ARARIQLWAPNYYGMDV 142 2264  296 GCGAGAGCCCGGATACAGCTCTGGGCACCAAATTACTACGGTATGGACG TC 142 2265  297 GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCCAGTCATGGCATTACCAGTTATTTAG CCTGGTATCAGCAAAAACCAGGGAATGCCCCTAAGCTCCTGATCTATGC TGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGG TCTGAGACACAGTTCACTCTCACAATCAGCGGCCTGCAGCCTGAAGATTT TGCAACTTATTACTGTCAACAGCTTAATCGTTACCCTCTAACGTTCGGCC AAGGGACCAAGGTGGAAATCAAA 142 2266  298 DIQLTQSPSFLSASVGDRVTITCRASHGITSYLAWYQQKPGNAPKLLIYAAST LQSGVPSRFSGSGSETQFTLTISGLQPEDFATYYCQQLNRYPLTFGQGTKVEI K 142 2267  299 RASHGITSYLA 142 2268  300 CGGGCCAGTCATGGCATTACCAGTTATTTAGCC 142 2269  301 AASTLQS 142 2270  302 GCTGCATCCACTTTGCAAAGT 142 2271  303 QQLNRYPLT 142 2272  304 CAACAGCTTAATCGTTACCCTCTAACG 143 2273  305 CAGGTCCAGCTTGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGATCTCCTGCAAGACCTCTGGTTACACCTTTACGAGCTCTGTG ATCAGCTGGGTGCGGCAGGCCCCTGGACAAGGGCTTGAGTGGGTGGGAT GGATCACCGGTCACAGAAGTAGCACAAACTATGCACAGAGACTCCAGG GTAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTATATGGA GCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGAGA GCCGATGGTGGTTCGGGGAGTTATTATAGCGCCTGGGGCCAGGGAACCC TGGTCACCGTCTCCTCA 143 2274  306 QVQLVQSGAEVKKPGASVKISCKTSGYTFTSSVISWVRQAPGQGLEWVGWI TGHRSSTNYAQRLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARADG GSGSYYSAWGQGTLVTVSS 143 2275  307 YTFTSSVIS 143 2276  308 TACACCTTTACGAGCTCTGTGATCAGC 143 2277  309 WITGHRSSTNYAQRLQG 143 2278  310 TGGATCACCGGTCACAGAAGTAGCACAAACTATGCACAGAGACTCCAGG GT 143 2279  311 ARADGGSGSYYSA 143 2280  312 GCGAGAGCCGATGGTGGTTCGGGGAGTTATTATAGCGCC 143 2281  313 TCCTATGAGCTGACACAGCCACCCTCAGCGTCAGTGGCCCCAGGAAAGA CGGCCAGGATCTCCTGTGGGGGAAACAACATTGGAACTAAGAGTGTCCA CTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTCTTGGTCATCTATCAT GATAGCCACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTC TGGGAACACGGCCACCCTGACCATCAGTAGGGTCGAAGCCGGGGATGA GGCCGACTATTATTGTCAGCTGTGGGATAGTAGTAGTGATTCCCATGTCT TCGGAACTGGGACCAAGCTCACCGTCCTA 143 2282  314 SYELTQPPSASVAPGKTARISCGGNNIGTKSVHWYQQKPGQAPVLVIYHDS HRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQLWDSSSDSHVFGTGT KLTVL 143 2283  315 GGNNIGTKSVH 143 2284  316 GGGGGAAACAACATTGGAACTAAGAGTGTCCAC 143 2285  317 HDSHRPS 143 2286  318 CATGATAGCCACCGGCCCTCA 143 2287  319 QLWDSSSDSHV 143 2288  320 CAGCTGTGGGATAGTAGTAGTGATTCCCATGTC 144 2289  321 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCGGGATTCACCATCAGTGGTTATAAC ATGTTCTGGGTCCGCCAGCCTCCGGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGGC CGTTTCATCGTCTCCAGAGACAACGCCAAGAATTCACTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTTCTGTGCGAGAGCA CCTCTTTTACCCGCTATGATGGACCTCTGGGGCCAAGGGACCACGGTCAC CGTCTCCTCA 144 2290  322 QVQLVQSGGGLVKPGGSLRLSCAASGFTISGYNMFWVRQPPGKGLEWVSSI TAGSSYLNYADSVKGRFIVSRDNAKNSLYLQMNSLRAEDTAVYFCARAPLL PAMMDLWGQGTTVTVSS 144 2291  323 FTISGYNMF 144 2292  324 TTCACCATCAGTGGTTATAACATGTTC 144 2293  325 SITAGSSYLNYADSVKG 144 2294  326 TCCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGG C 144 2295  327 ARAPLLPAMMDL 144 2296  328 GCGAGAGCACCTCTTTTACCCGCTATGATGGACCTC 144 2297  329 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATCTATACTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCCTGAATGG TTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 144 2298  330 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYT NNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLNGYVFG TGTKLTVL 144 2299  331 TGSSSNIGAGYDVH 144 2300  332 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 144 2301  333 TNNNRPS 144 2302  334 ACTAACAACAATCGGCCCTCA 144 2303  335 QSYDRSLNGYV 144 2304  336 CAGTCCTATGACAGAAGCCTGAATGGTTATGTC 145 2305  337 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT CACTGATGGTCTCCTGCTCGGCTTCTGGATACATTTTCAACAGTGACATC AACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGGTGG ATGAACCCTAAGAATGGTCACACAGGCTATGCACAGGAATTCGAGGGCA GAGTCAGCATGACCAGGAACTCCTCCAAAACTATTGCCTATCTGCAGCT GAGCAGCCTGACATATGAAGACACGGCCGTCTATTATTGTGTTTACGATT TCTGGAGTGATGATTCAGTCAAGTGGGGCCGGGGAACCCTGGTCACCGT CTCCTCA 145 2306  338 QVQLVQSGAEVKKPGASLMVSCSASGYIFNSDINWVRQAPGQGLEWMGW MNPKNGHTGYAQEFEGRVSMTRNSSKTIAYLQLSSLTYEDTAVYYCVYDF WSDDSVKWGRGTLVTVSS 145 2307  339 YIFNSDIN 145 2308  340 TACATTTTCAACAGTGACATCAAC 145 2309  341 WMNPKNGHTGYAQEFEG 145 2310  342 TGGATGAACCCTAAGAATGGTCACACAGGCTATGCACAGGAATTCGAGG GC 145 2311  343 VYDFWSDDSVK 145 2312  344 GTTTACGATTTCTGGAGTGATGATTCAGTCAAG 145 2313  345 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GTGTCGCCATCTCCTGCTCTGGGAGCAGCTCCAACATCGGGCCAGGTTAT GATGTACACTGGTACCAGCAACTTCCGGGATCAGCCCCCAAACTCCTCA TCTACGGTGACAACAATCGGCCCTCAGGGGTCCCTGAGCGATTCTCTACC TCCAAGTCTGGCACCTCAGCCTCACTGGCCATCACTGGGCTCCAGGCTGA GGATGAGGCTGATTATTACTGCCAGTCCTTTGACAGCAGCCTGCGTGGTT ATGTCTTCGGAACTGGGACCAAGGTGACCGTCCTA 145 2314  346 QSVVTQPPSVSGAPGQSVAISCSGSSSNIGPGYDVHWYQQLPGSAPKLLIYG DNNRPSGVPERFSTSKSGTSASLAITGLQAEDEADYYCQSFDSSLRGYVFGT GTKVTVL 145 2315  347 SGSSSNIGPGYDVH 145 2316  348 TCTGGGAGCAGCTCCAACATCGGGCCAGGTTATGATGTACAC 145 2317  349 GDNNRPS 145 2318  350 GGTGACAACAATCGGCCCTCA 145 2319  351 QSFDSSLRGYV 145 2320  352 CAGTCCTTTGACAGCAGCCTGCGTGGTTATGTC 146 2321  353 CAGGTCCAGCTGGTACAGTCTGGAGCAGCGGTGAAAAAGCCCGGGGAG TCTCTGAAGATCTCCTGTAAGGGTTTTGGATACAGCTTTACCAAGTATTG GATCGGCTGGGTGCGCCAGGTGCCCGGGAAAGGCCTGGAGTGGATAGG GATCATCTCTCCTACTGACTCTAATACCAGATACAGCCCGTCCTTCCGAG GCCAGGTCACCATGTCAGCCGACAAGTCCATCAGTGCCGCCTACCTGCA GTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGA CACAGCAGTCCGTATAGCAGTGGCTGGTACGGAGATACATACTTCTTTG ACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 146 2322  354 QVQLVQSGAAVKKPGESLKISCKGFGYSFTKYWIGWVRQVPGKGLEWIGII SPTDSNTRYSPSFRGQVTMSADKSISAAYLQWSSLKASDTAMYYCARHSSP YSSGWYGDTYFFDSWGQGTLVTVSS 146 2323  355 YSFTKYWIG 146 2324  356 TACAGCTTTACCAAGTATTGGATCGGC 146 2325  357 IISPTDSNTRYSPSFRG 146 2326  358 ATCATCTCTCCTACTGACTCTAATACCAGATACAGCCCGTCCTTCCGAGG C 146 2327  359 ARHSSPYSSGWYGDTYFFDS 146 2328  360 GCGAGACACAGCAGTCCGTATAGCAGTGGCTGGTACGGAGATACATACT TCTTTGACTCC 146 2329  361 CAGCCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGA GGGTCACCATCTCTTGTTCTGGAAGCAACTCCAACATCGGGACTAATACT GTGAACTGGTACCAGCAGCTCCCTGGAACGGCCCCCAAAGTCCTCATCC ATAATAATAATGAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC AAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGG ATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGAGGTTA TGTCTTCGGAACTGGGACCAAGGTGACCGTCCTA 146 2330  362 QPVLTQPPSASGTPGQRVTISCSGSNSNIGTNTVNWYQQLPGTAPKVLIHNN NERPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLRGYVFGT GTKVTVL 146 2331  363 SGSNSNIGTNTVN 146 2332  364 TCTGGAAGCAACTCCAACATCGGGACTAATACTGTGAAC 146 2333  365 NNNERPS 146 2334  366 AATAATAATGAGCGGCCCTCA 146 2335  367 AAWDDSLRGYV 146 2336  368 GCAGCATGGGATGACAGCCTGAGAGGTTATGTC 147 2337  369 CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCGGCAGCTATGC TATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGA GGGACCATCCCTATCTTTGGTACAGCAGACCACGCACAGAAGTTCCAGG GCAGAGTCACGATAACCGCGGACAAATCCACGAGCACAGCGTACATGG AACTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAG AGGTGTTTTCCGCGTAGGTTGTAGTGATACCAGCTGCCTCAAAAACTACT ACGGTACGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 147 2338  370 QVQLVQSGAEVKKPGSSVKVSCKASGGTFGSYAISWVRQAPGQGLEWMG GTIPIFGTADHAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGVF RVGCSDTSCLKNYYGTDVWGQGTTVTVSS 147 2339  371 GTFGSYAIS 147 2340  372 GGCACCTTCGGCAGCTATGCTATCAGC 147 2341  373 GTIPIFGTADHAQKFQG 147 2342  374 GGGACCATCCCTATCTTTGGTACAGCAGACCACGCACAGAAGTTCCAGG GC 147 2343  375 ARGVFRVGCSDTSCLKNYYGTDV 147 2344  376 GCGAGAGGTGTTTTCCGCGTAGGTTGTAGTGATACCAGCTGCCTCAAAA ACTACTACGGTACGGACGTC 147 2345  377 CAGTCTGTTCTGATTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTC GATCACCGTCTCCTGCACTGGATCCAGCGGTGACGTTGGTGCTTATAAGT ATGTCTCCTGGTACCAACAACACCCAGGCAGAGGCCCCAAACTCATAAT TTATGATGTCAGTGCTCGGCCCTCAGGGATTTCTGATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA GGACGAGGCTGACTATTACTGCAGCTCATATTCAAGCAGCAGCACTCTC GTAGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 147 2346  378 QSVLIQPASVSGSPGQSITVSCTGSSGDVGAYKYVSWYQQHPGRGPKLIIYD VSARPSGISDRFSGSKSGNTASLTISGLQAEDEADYYCSSYSSSSTLVVFGGG TKVTVL 147 2347  379 TGSSGDVGAYKYVS 147 2348  380 ACTGGATCCAGCGGTGACGTTGGTGCTTATAAGTATGTCTCC 147 2349  381 DVSARPS 147 2350  382 GATGTCAGTGCTCGGCCCTCA 147 2351  383 SSYSSSSTLVV 147 2352  384 AGCTCATATTCAAGCAGCAGCACTCTCGTAGTA 148 2353  385 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGGTTGGTGCAGCCTGGGGGGT CCCTGAGACTCTCTTGTGTAGGCTCTGGATTCACCTTCAGTACCTATAGT ATGAACTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAC ACATTAGTAGTAGTAGTGTTACCATGTACTACGCAGACTTTGTGAAGGG CCGATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAA ATGACCAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAG ATGCGGGACCAGTTTGGAGTGGTTATTACGACTACGGTATGGACGTCTG GGGCCAAGGGACCACGGTCACTGTCTCCTCA 148 2354  386 QVQLVQSGGGLVQPGGSLRLSCVGSGFTFSTYSMNWVRQAPGKGLEWVSH ISSSSVTMYYADFVKGRFTISRDNAKNSLYLQMTSLRAEDTAVYYCARDAG PVWSGYYDYGMDVWGQGTTVTVSS 148 2355  387 FTFSTYSMN 148 2356  388 TTCACCTTCAGTACCTATAGTATGAAC 148 2357  389 HISSSSVTMYYADFVKG 148 2358  390 CACATTAGTAGTAGTAGTGTTACCATGTACTACGCAGACTTTGTGAAGG GC 148 2359  391 ARDAGPVWSGYYDYGMDV 148 2360  392 GCGAGAGATGCGGGACCAGTTTGGAGTGGTTATTACGACTACGGTATGG ACGTC 148 2361  393 GAAACGACACTCACGCAGTCTCCAGCCACGCTGTCTTTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCCTCTT AGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATTTTTG ATGCATCCAAGAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTCTATTACTGTCAGCAGCGTTACAACTGGCCTCCGCTCACTTT CGGCGGAGGGACCAAGGTGGAAATCAAA 148 2362  394 ETTLTQSPATLSLSPGERATLSCRASQSVSSLLAWYQQKPGQAPRLLIFDASK RATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRYNWPPLTFGGGTKV EIK 148 2363  395 RASQSVSSLLA 148 2364  396 AGGGCCAGTCAGAGTGTTAGCAGCCTCTTAGCC 148 2365  397 DASKRAT 148 2366  398 GATGCATCCAAGAGGGCCACT 148 2367  399 QQRYNWPPLT 148 2368  400 CAGCAGCGTTACAACTGGCCTCCGCTCACT 149 2369  401 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGCAGGT CCCTGAGACTCTCCTGTGCAGCCTTTGGATTCACCTTTGATGATTATGCC ATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAG GTATTAGTTGGAATAGTGGTTTCATAGGCTATGCGGACTCTGTGAAGGG CCGATTCACCATCTCCAGAGACAATGCCAAGAACTCCCTGTCTCTGCAA ATGAACAGTCTGAGAACTGAGGATACGGCCTTGTATTACTGTGCAAAAA CTGATGGAGCAGTGGCTGTCGACGGGCCCTTTGACTACTGGGGCCAGGG AACCCTGGTCACCGTCTCCTCA 149 2370  402 EVQLVESGGGLVQPGRSLRLSCAAFGFTFDDYAMHWVRQAPGKGLEWVS GISWNSGFIGYADSVKGRFTISRDNAKNSLSLQMNSLRTEDTALYYCAKTD GAVAVDGPFDYWGQGTLVTVSS 149 2371  403 FTFDDYAMH 149 2372  404 TTCACCTTTGATGATTATGCCATGCAC 149 2373  405 GISWNSGFIGYADSVKG 149 2374  406 GGTATTAGTTGGAATAGTGGTTTCATAGGCTATGCGGACTCTGTGAAGG GC 149 2375  407 AKTDGAVAVDGPFDY 149 2376  408 GCAAAAACTGATGGAGCAGTGGCTGTCGACGGGCCCTTTGACTAC 149 2377  409 GAAATTGTGTTGACACAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTATTTA AGTTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATT CTACATCTAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAGGATT TTGCAACTTACTACTGTCAACAGAGTTACATTGCCCCTCCGACTTTTGGC CAGGGGACCAAGGTGGAAATCAAA 149 2378  410 EIVLTQSPSSLSASVGDRVTITCRASQSISGYLSWYQQKPGKAPKLLIHSTSSL QSGVPSRFSGSGSGTDFTLTITSLQPEDFATYYCQQSYIAPPTFGQGTKVEIK 149 2379  411 RASQSISGYLS 149 2380  412 CGGGCAAGTCAGAGCATTAGCGGCTATTTAAGT 149 2381  413 STSSLQS 149 2382  414 TCTACATCTAGTTTGCAAAGT 149 2383  415 QQSYIAPPT 149 2384  416 CAACAGAGTTACATTGCCCCTCCGACT 150 2385  417 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGATGAAGGTCTCCTGCCAGGCTTCTGGAGGCCCCTTCAGCACCTATACT ATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GTATCATCCCTGTCTTTGGTACACCAAACTACGCGCAGAAGTTCCACGGC AGAGTCACGATTACCGCGGACCAATCCACGAGCACAGCCTACATGGAGT TGAGTAGCCTGAGATCTGAGGACACCGCCGTTTATTACTGTGCGGGAGC CCCCTACCCTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCC TCA 150 2386  418 QVQLVQSGAEVKKPGSSMKVSCQASGGPFSTYTISWVRQAPGQGLEWMGG IIPVFGTPNYAQKFHGRVTITADQSTSTAYMELSSLRSEDTAVYYCAGAPYP MDVWGQGTTVTVSS 150 2387  419 GPFSTYTIS 150 2388  420 GGCCCCTTCAGCACCTATACTATCAGC 150 2389  421 GIIPVFGTPNYAQKFHG 150 2390  422 GGTATCATCCCTGTCTTTGGTACACCAAACTACGCGCAGAAGTTCCACGG C 150 2391  423 AGAPYPMDV 150 2392  424 GCGGGAGCCCCCTACCCTATGGACGTC 150 2393  425 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA GAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGCCAGCTCCTTA GCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGCGTACCAACTGGCAGGGGCTCTCTTT CGGCGGAGGGACCAAAGTGGATATCAAA 150 2394  426 EIVLTQSPATLSLSPGERATLSCRASQSVASSLAWYQQKPGQAPRLLIYDAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRTNWQGLSFGGGTK VDIK 150 2395  427 RASQSVASSLA 150 2396  428 AGGGCCAGTCAGAGTGTTGCCAGCTCCTTAGCC 150 2397  429 DASNRAT 150 2398  430 GATGCATCCAACAGGGCCACT 150 2399  431 QQRTNWQGLS 150 2400  432 CAGCAGCGTACCAACTGGCAGGGGCTCTCT 151 2401  433 CAGGTCCAGCTTGTGCAGTCTGGAGGTGAGGTCAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTATCAGTTATGGT ATCACCTGGGTGCGACAGGCCCCTGGACAAGGGCCTGAGTGGATGGGAT GGATCAGCCCTTACAACGGTGACACAAACTATGCACAGAAGCTCCAGGG CAGAGTCACCATGACCACAGACACATCCACGACCACAGCCTACATGGAA CTGAGGAGCCTGAGATCTGACGACACGGCCATATATTATTGTGCGAGAC GGTACGATATTTTGACTGGCGGGGGCTGGTTCGACTCCTGGGGCCAGGG AACCCTGGTCACCGTCTCCTCA 151 2402  434 QVQLVQSGGEVKKPGASVKVSCKASGYTFISYGITWVRQAPGQGPEWMG WISPYNGDTNYAQKLQGRVTMTTDTSTTTAYMELRSLRSDDTAIYYCARR YDILTGGGWFDSWGQGTLVTVSS 151 2403  435 YTFISYGIT 151 2404  436 TACACCTTTATCAGTTATGGTATCACC 151 2405  437 WISPYNGDTNYAQKLQG 151 2406  438 TGGATCAGCCCTTACAACGGTGACACAAACTATGCACAGAAGCTCCAGG GC 151 2407  439 ARRYDILTGGGWFDS 151 2408  440 GCGAGACGGTACGATATTTTGACTGGCGGGGGCTGGTTCGACTCC 151 2409  441 GATATTGTGATGACTCAGTCTCCTTCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCAATTGCCGGGCAAGTCAGAGCATTATCAGCTATTTA AATTGGTATCAGCAAAAACCAGGGAAAGCCCCTGAGCTCCTAATCTATG CTGCGTCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGAGTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGAT TTTGCAACGTACTACTGTCAACAGAGTTACAGTACCCCTCTTAGTTTCGG CCCTGGGACCAAGGTGGAGATCAAA 151 2410  442 DIVMTQSPSSLSASVGDRVTINCRASQSIISYLNWYQQKPGKAPELLIYAASS LQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQSYSTPLSFGPGTKVEIK 151 2411  443 RASQSIISYLN 151 2412  444 CGGGCAAGTCAGAGCATTATCAGCTATTTAAAT 151 2413  445 AASSLQS 151 2414  446 GCTGCGTCCAGTTTGCAAAGT 151 2415  447 QQSYSTPLS 151 2416  448 CAACAGAGTTACAGTACCCCTCTTAGT 152 2417  449 CAGGTCCAGCTTGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGT CTCTGAAGATCTCCTGTAAGACTTCTGGATACAAATTTACCAATTACTGG ATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGG ATCATCTATCCTGGTGACTCTGATGCCAGATACAGCCCGTCCTTCCAAGG CCAGGTCACCTTCTCAGCCGACAAGTCCATCAGCACCGCCTACCTGCAGT GGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGACA AGATAACAGTGGCTGGGCCGACTTCTTTCCCTTTGACTACTGGGGCCAGG GAACCCTGGTCACCGTCTCCTCA 152 2418  450 QVQLVQSGAEVKKPGESLKISCKTSGYKFTNYWIGWVRQMPGKGLEWMGI IYPGDSDARYSPSFQGQVTFSADKSISTAYLQWSSLKASDTAMYYCARQDN SGWADFFPFDYWGQGTLVTVSS 152 2419  451 YKFTNYWIG 152 2420  452 TACAAATTTACCAATTACTGGATCGGC 152 2421  453 ITYPGDSDARYSPSFQG 152 2422  454 ATCATCTATCCTGGTGACTCTGATGCCAGATACAGCCCGTCCTTCCAAGG C 152 2423  455 ARQDNSGWADFFPFDY 152 2424  456 GCGAGACAAGATAACAGTGGCTGGGCCGACTTCTTTCCCTTTGACTAC 152 2425  457 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCACAGTTTTAGCAGCAGCTA CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGCTGCATCCAACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAG TGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAA GATTTTGCAGTGTATTTCTGTCAGCAGTATGATAGCTCACCGTGGACGTT CGGCCAAGGGACCAAGGTGGAGATCAAA 152 2426  458 ETTLTQSPGTLSLSPGERATLSCRASHSFSSSYLAWYQQKPGQAPRLLIYAAS NRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYFCQQYDSSPWTFGQGTKVE IK 152 2427  459 RASHSFSSSYLA 152 2428  460 AGGGCCAGTCACAGTTTTAGCAGCAGCTACTTAGCC 152 2429  461 AASNRAT 152 2430  462 GCTGCATCCAACAGGGCCACT 152 2431  463 QQYDSSPWT 152 2432  464 CAGCAGTATGATAGCTCACCGTGGACG 153 2433  465 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAAAT CCCTGAGACTCTCCTGTGCCGCGTCGGGATTCATCTTCAGTGGCTATGGC ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCGT TTATATGGTTTGATGGAAGTTCTACATATTATGCAGACTCCGTGAAGGGC CGTTTCACCATCTCCAAAGACGATTCCAAGCAGACGGTATATTTGCAAAT GAACAGGCTGAGAGCCGAGGACACGGCTGTCTACTACTGTGCGAGAGAC CCCTTATTTTTATACAATTATAATGACGAACCTTTTGACTACTGGGGACA GGGAACCCTGGTCACCGTCTCCTCA 153 2434  466 EVQLVESGGGVVQPGKSLRLSCAASGFIFSGYGMHWVRQAPGKGLEWVAF IWFDGSSTYYADSVKGRFTISKDDSKQTVYLQMNRLRAEDTAVYYCARDPL FLYNYNDEPFDYWGQGTLVTVSS 153 2435  467 FIFSGYGMH 153 2436  468 TTCATCTTCAGTGGCTATGGCATGCAC 153 2437  469 FIWFDGSSTYYADSVKG 153 2438  470 TTTATATGGTTTGATGGAAGTTCTACATATTATGCAGACTCCGTGAAGGG C 153 2439  471 ARDPLFLYNYNDEPFDY 153 2440  472 GCGAGAGACCCCTTATTTTTATACAATTATAATGACGAACCTTTTGACTA C 153 2441  473 TCCTATGAGCTGACACAGCCACCCTCAGCGTCTGGTTCCCCCGGGCAGA GCGTCACCATCTCTTGTTCTGGAAGCAGCTCCAATATCGGGGGTAATTTT GTGTACTGGTACCAGCAACTGCCCGGAACGGCCCCCAAAGTCCTCATCT ATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTC CAAGTCTGGCACTTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGACG ATGAGGCTGATTATTATTGTTCAGTATGGGATGACAGCCTAAATGGTCG GCTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 153 2442  474 SYELTQPPSASGSPGQSVTISCSGSSSNIGGNFVYWYQQLPGTAPKVLIYRNN QRPSGVPDRFSGSKSGTSASLAISGLRSDDEADYYCSVWDDSLNGRLFGGG TKLTVL 153 2443  475 SGSSSNIGGNFVY 153 2444  476 TCTGGAAGCAGCTCCAATATCGGGGGTAATTTTGTGTAC 153 2445  477 RNNQRPS 153 2446  478 AGGAATAATCAGCGGCCCTCA 153 2447  479 SVWDDSLNGRL 153 2448  480 TCAGTATGGGATGACAGCCTAAATGGTCGGCTG 154 2449  481 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGTGTGGTCCGGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAAGTTTGATGATTATGGC ATGAGCTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGAGTGGGTCTCTG CAATTATTTGGAATAGTGGTAGCACAGGTTATGCAGACTCTGTGAAGGG CCGATTCATCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAA ATGAATAGTCTGAGAGCCGAAGACACGGCCTTGTATTACTGTGCGAGAG TCGGGGGGATAACGAAGTGGTGGTACTACGGTATGGACCTCTGGGGCCA AGGGACCACGGTCACCGTCTCCTCA 154 2450  482 EVQLVESGGGVVRPGGSLRLSCAASGFKFDDYGMSWVRQAPGKGLEWVS AIIWNSGSTGYADSVKGRFIISRDNAKNSLYLQMNSLRAEDTALYYCARVG GITKWWYYGMDLWGQGTTVTVSS 154 2451  483 FKFDDYGMS 154 2452  484 TTCAAGTTTGATGATTATGGCATGAGC 154 2453  485 AIIWNSGSTGYADSVKG 154 2454  486 GCAATTATTTGGAATAGTGGTAGCACAGGTTATGCAGACTCTGTGAAGG GC 154 2455  487 ARVGGITKWWYYGMDL 154 2456  488 GCGAGAGTCGGGGGGATAACGAAGTGGTGGTACTACGGTATGGACCTC 154 2457  489 GAAACGACACTCACGCAGTCTCCATCCTTCCTGTCTGCATCTGTCGGAGA CAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCTTGAGCAATTATTTA GCCTGGTATCAGCAAAAACCAGGGAGAGCCCCCAAGCTCCTGATCTATG CTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGAGGCAGTGG ATCTGGGACAGAGTTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGAT CTTGCAACTTATTACTGTCAACACCTTAATAGTTACCCTCTCACTTTCGGC GGAGGGACCAAGGTGGAGATCAAA 154 2458  490 ETTLTQSPSFLSASVGDRVTITCRASQGLSNYLAWYQQKPGRAPKLLIYAAS TLQSGVPSRFRGSGSGTEFTLTISSLQPEDLATYYCQHLNSYPLTFGGGTKVE IK 154 2459  491 RASQGLSNYLA 154 2460  492 CGGGCCAGTCAGGGCTTGAGCAATTATTTAGCC 154 2461  493 AASTLQS 154 2462  494 GCTGCATCCACTTTGCAAAGT 154 2463  495 QHLNSYPLT 154 2464  496 CAACACCTTAATAGTTACCCTCTCACT 155 2465  497 GAGGTGCAGCTGGTGGAGTCGGGCCCCGGACTGGTGAAGCCTTCGGAGA CCCTGTCCCTCATCTGCAGAGTCTTTGGTGGGTCCGTCAGGAGGGGGGA CTACAACTGGAATTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGG ATTGGCTATATCGATTATAGTGGGACCACCAAGTACAATCCCTCCCTCAA GAGCCGAGTGACCATATCAGAAGACACGTCCAGGAATCAGTTCTCCCTG GAGCTGAGGTCTGTGACCGCCGCGGACACGGCCATGTATTACTGTGCGA GAGACGTTGGAAGTACTCCCTACAACTATTACGGTATGGACGTCTGGGG CCAAGGGACCACGGTCACCGTCTCCTCA 155 2466  498 EVQLVESGPGLVKPSETLSLICRVFGGSVRRGDYNWNWIRQPPGKGLEWIG YIDYSGTTKYNPSLKSRVTISEDTSRNQFSLELRSVTAADTAMYYCARDVGS TPYNYYGMDVWGQGTTVTVSS 155 2467  499 GSVRRGDYNWN 155 2468  500 GGGTCCGTCAGGAGGGGGGACTACAACTGGAAT 155 2469  501 YIDYSGTTKYNPSLKS 155 2470  502 TATATCGATTATAGTGGGACCACCAAGTACAATCCCTCCCTCAAGAGC 155 2471  503 ARDVGSTPYNYYGMDV 155 2472  504 GCGAGAGACGTTGGAAGTACTCCCTACAACTATTACGGTATGGACGTC 155 2473  505 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCCTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGTAGGGCCAGTCAGACTATTAAAAACAACTAC TTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATGT ATGGTGTATCCAGCAGGCCGACTGGCATCCCAGACAGGTTCAGTGGCAG TGGGTCTGGGACAGACTTCAGTCTCACCATCGACAGACTGGAGCCTGAA GATTTTGCAGTATATTACTGTCAGCAGTTTGGTAGGTCACCGGAGCTCAC TTTCGGCGGAGGGACCAAGGTGGAAATCAAA 155 2474  506 EIVLTQSPGTLSLSPGERATLSCRASQTIKNNYLAWYQQKPGQAPRLLMYG VSSRPTGIPDRFSGSGSGTDFSLTIDRLEPEDFAVYYCQQFGRSPELTFGGGT KVEIK 155 2475  507 RASQTIKNNYLA 155 2476  508 AGGGCCAGTCAGACTATTAAAAACAACTACTTAGCC 155 2477  509 GVSSRPT 155 2478  510 GGTGTATCCAGCAGGCCGACT 155 2479  511 QQFGRSPELT 155 2480  512 CAGCAGTTTGGTAGGTCACCGGAGCTCACT 156 2481  513 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGA CCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTAC TGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG GAAGTCAATCATAGTGGAACCTCCAATTACAACCCGTCCCTCACGAGTC GAGTCACCATATCAGTAGACCCGTCCAAGAAACAGTTGTCCCTGAAGCT GAACTCTGTGACCGCCGCGGACACGGCTGTCTATTACTGTGCGAGAGCT CCTTGGTATACTCACGCCATGGACGTCTGGGGCCAAGGGACCACGGTCA CCGTCTCCTCA 156 2482  514 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWGWIRQPPGKGLEWIGE VNHSGTSNYNPSLTSRVTISVDPSKKQLSLKLNSVTAADTAVYYCARAPWY THAMDVWGQGTTVTVSS 156 2483  515 GSFSGYYWG 156 2484  516 GGGTCCTTCAGTGGTTACTACTGGGGC 156 2485  517 EVNHSGTSNYNPSLTS 156 2486  518 GAAGTCAATCATAGTGGAACCTCCAATTACAACCCGTCCCTCACGAGT 156 2487  519 ARAPWYTHAMDV 156 2488  520 GCGAGAGCTCCTTGGTATACTCACGCCATGGACGTC 156 2489  521 CAGTCTGTCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTC GATCACCATCTCCTGCACTAGAACCAGCAGTGACGTTGGTGCTTATAGTT ATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATGAT TTATGATGTCAATAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA GGACGAGGCTGATTATTACTGCAGCTCATATACAAACAGCAACACTCTC GGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 156 2490  522 QSVLTQPASVSGSPGQSITISCTRTSSDVGAYSYVSWYQQHPGKAPKLMIYD VNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTNSNTLGVFGG GTKLTVL 156 2491  523 TRTSSDVGAYSYVS 156 2492  524 ACTAGAACCAGCAGTGACGTTGGTGCTTATAGTTATGTCTCC 156 2493  525 DVNNRPS 156 2494  526 GATGTCAATAATCGGCCCTCA 156 2495  527 SSYTNSNTLGV 156 2496  528 AGCTCATATACAAACAGCAACACTCTCGGGGTG 157 2497  529 GAGGTGCAGCTGTTGGAGTCTGGGGGACTCGTGGTACAGCCTGGGGGGT CCCTGAGACTGTCCTGTGCAGCCTCTGGATTCATCTTTGATGATTATACC ATGCACTGGGTCCGTCAAGCTCCGGGGAAGGGTCTGGAGTGGATCTCTC TTATTAGTTGGGATAGTCTTGACACATACTATGCAGGCTCTGTGCAGGGC CGCTTCACCATCTCCAGAGACAACAGCAGAAACTCCCTCTATCTGCGAA TGAACAGTCTGAGACCTGAGGACACCGCCTTGTATTACTGTGCAAAAAC AAAGTATAGGGGTACTTATTACTACTTTGACTCGTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA 157 2498  530 EVQLLESGGLVVQPGGSLRLSCAASGFIFDDYTMHWVRQAPGKGLEWISLIS WDSLDTYYAGSVQGRFTISRDNSRNSLYLRMNSLRPEDTALYYCAKTKYR GTYYYFDSWGQGTLVTVSS 157 2499  531 FIFDDYTMH 157 2500  532 TTCATCTTTGATGATTATACCATGCAC 157 2501  533 LISWDSLDTYYAGSVQG 157 2502  534 CTTATTAGTTGGGATAGTCTTGACACATACTATGCAGGCTCTGTGCAGGG C 157 2503  535 AKTKYRGTYYYFDS 157 2504  536 GCAAAAACAAAGTATAGGGGTACTTATTACTACTTTGACTCG 157 2505  537 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTATTTA AATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACG ATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGACGTGG ATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGATA TTGCAACATATTACTGTCAACAATATGATAATCTCCCTCCGGTCACTTTC GGCCCTGGGACCAAGGTGGAAATCAAA 157 2506  538 DIRVTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDAS NLETGVPSRFSGRGSGTDFTFTISSLQPEDIATYYCQQYDNLPPVTFGPGTKV EIK 157 2507  539 QASQDISNYLN 157 2508  540 CAGGCGAGTCAGGACATTAGCAACTATTTAAAT 157 2509  541 DASNLET 157 2510  542 GATGCATCCAATTTGGAAACA 157 2511  543 QQYDNLPPVT 157 2512  544 CAACAATATGATAATCTCCCTCCGGTCACT 158 2513  545 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGTTATGGC ATGCACTGGGTCCGCCAGGCGCCAGGGAAGGGGCTAGAGTGGGTCTCAT CCATTACTGCTGGTAGTAGTTACATGGACTACGCAGACTCAGTGAAGGG CCGATTCACCGTCTCCAGAGACAACGGCAAGAACTCACTGTACCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTACTTCTGTGCGAGAG AGGACTATGATAGTCGTGTTTATTACCTTAAGTGGTTCGACCCCTGGGGC CAGGGAACCCTGGTCACCGTCTCCTCA 158 2514  546 EVQLLESGGGLVKPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSSI TAGSSYMDYADSVKGRFTVSRDNGKNSLYLQMNSLRAEDTAVYFCAREDY DSRVYYLKWFDPWGQGTLVTVSS 158 2515  547 FTFSSYGMH 158 2516  548 TTCACCTTCAGTAGTTATGGCATGCAC 158 2517  549 SITAGSSYMDYADSVKG 158 2518  550 TCCATTACTGCTGGTAGTAGTTACATGGACTACGCAGACTCAGTGAAGG GC 158 2519  551 AREDYDSRVYYLKWFDP 158 2520  552 GCGAGAGAGGACTATGATAGTCGTGTTTATTACCTTAAGTGGTTCGACCC C 158 2521  553 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GAGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGACAGGTTA TGATGTACACTGGTACCAGCAGCTTCCAGGATCAGCCCCCAAACTCCTC ATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG GTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGACTATTATTGCCAGTCCTATGACAGCAGTCGGAGTGG TTATGTCTTCGGAACTGGGACCAAGCTGACCGTCCTA 158 2522  554 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDVHWYQQLPGSAPKLLIYG NSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSRSGYVFGT GTKLTVL 158 2523  555 TGSSSNIGTGYDVH 158 2524  556 ACTGGGAGCAGCTCCAACATCGGGACAGGTTATGATGTACAC 158 2525  557 GNSNRPS 158 2526  558 GGTAACAGCAATCGGCCCTCA 158 2527  559 QSYDSSRSGYV 158 2528  560 CAGTCCTATGACAGCAGTCGGAGTGGTTATGTC 159 2529  561 GAGGTGCAGCTGGTGGAGTCTGGGGGCGCCTTGGTAAAGCCGGGGGGGT CCCTTAGACTCTCCTGTGTAGGCACTGGACTCACTTTCACTACTGCCTAC ATGAGCTGGGCCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGTC GCATTAAGAGCAAAAGTGATGGTGGGACAACAGAGTACCCTACACCCGT CAAAGGCAGATTCACCATCTCAAGAGATGAATCCAAAAACACCCTGTAT CTGCAAATGAACAGCCTGAAAATCGAGGACACAGCCGTCTATTATTGTA CCACAGATAGGGGGATAACAGCTCGTCCTATCTTCGACTCCTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 159 2530  562 EVQLVESGGALVKPGGSLRLSCVGTGLTFTTAYMSWARQAPGKGLEWVGR IKSKSDGGTTEYPTPVKGRFTISRDESKNTLYLQMNSLKIEDTAVYYCTTDR GITARPIFDSWGQGTLVTVSS 159 2531  563 LTFTTAYMS 159 2532  564 CTCACTTTCACTACTGCCTACATGAGC 159 2533  565 RIKSKSDGGTTEYPTPVKG 159 2534  566 CGCATTAAGAGCAAAAGTGATGGTGGGACAACAGAGTACCCTACACCCG TCAAAGGC 159 2535  567 TTDRGITARPIFDS 159 2536  568 ACCACAGATAGGGGGATAACAGCTCGTCCTATCTTCGACTCC 159 2537  569 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCTAGGGCGGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACATTGGTACAGGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATTTATGGTAACACCAAACGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTATGCCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGACGCTGATTATTACTGCCAGTCCTATGACGGCGGCCTGAGTGG TTATGTCTTCGGAACTGGCACCCAGCTGACCGTCCTC 159 2538  570 QSVLTQPPSVSGALGRRVTISCTGSSSNIGAGYDVHWYRQLPGTAPKLLIYG NTKRPSGVPDRFSGSKYATSASLAITGLQAEDDADYYCQSYDGGLSGYVFG TGTQLTVL 159 2539  571 TGSSSNIGAGYDVH 159 2540  572 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAT 159 2541  573 GNTKRPS 159 2542  574 GGTAACACCAAACGGCCCTCA 159 2543  575 QSYDGGLSGYV 159 2544  576 CAGTCCTATGACGGCGGCCTGAGTGGTTATGTC 160 2545  577 CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCCTGGTCAGGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCATGTTCAGTACCTACAGC ATGAACTGGCTCCGCACGGTCCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTGGTAGTAGCAGTCACATATACTACGCAGACTCAGTGAAGGG CCGATTCACCATCTCCAGAGACAACACCAAGAACTCACTGTATCTGCAA ATGAACAGCCTGAGACCCGAAGACACGGCTTTATATTACTGTGCGAGAT ATTTTGGTGACTACTCAGGGTTGGGGAACTACTACTACTACGGTATGGAC GTCTGGGGCCAGGGGACCACGGTCACCGTCTCCTCA 160 2546  578 QVQLVQSGGGLVRPGGSLRLSCAASGFMFSTYSMNWLRTVPGKGLEWVSS ISGSSSHIYYADSVKGRFTISRDNTKNSLYLQMNSLRPEDTALYYCARYFGD YSGLGNYYYYGMDVWGQGTTVTVSS 160 2547  579 FMFSTYSMN 160 2548  580 TTCATGTTCAGTACCTACAGCATGAAC 160 2549  581 SISGSSSHIYYADSVKG 160 2550  582 TCCATTAGTGGTAGTAGCAGTCACATATACTACGCAGACTCAGTGAAGG GC 160 2551  583 ARYFGDYSGLGNYYYYGMDV 160 2552  584 GCGAGATATTTTGGTGACTACTCAGGGTTGGGGAACTACTACTACTACG GTATGGACGTC 160 2553  585 GATATTGTGATGACGCAGTCTCCAGTCTCCCTGCCCGTCACCCCTGGAGA GCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATTCTAATG GAAACAACTATTTGGATTGGTACCTGCAGAGGCCAGGGCAGTCTCCACA GCTCCTCATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGT TCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAGAATCAGCAGAGT GGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACT CCTCGCTTCGGCGGAGGGACCAAGGTGGAAATCAAA 160 2554  586 DIVMTQSPVSLPVTPGEPASISCRSSQSLLHSNGNNYLDWYLQRPGQSPQLLI YLGSNRASGVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCMQALQTPRFGG GTKVEIK 160 2555  587 RSSQSLLHSNGNNYLD 160 2556  588 AGGTCTAGTCAGAGCCTCCTGCATTCTAATGGAAACAACTATTTGGAT 160 2557  589 LGSNRAS 160 2558  590 TTGGGTTCTAATCGGGCCTCC 160 2559  591 MQALQTPR 160 2560  592 ATGCAAGCTCTACAAACTCCTCGC 161 2561  593 GAGGTGCAGCTGGTGGAGTCTGGGGGACACTTGGTACAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGT ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCAT ACATTAGTAGTAGTAGTAGTACCATGTACTACGCAGACTCTGTGAAGGG CCGATTCACCATGTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAA ATGAACAGCCTGAGAGACGAGGACACGGCTTTGTATTACTGTGCGAGAG ATTTCCCCCCTATTAATCTAGCAGCGACAACCCGAAACTACTACTACTAT GTTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 161 2562  594 EVQLVESGGHLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWISYI SSSSSTMYYADSVKGRFTMSRDNAKNSLYLQMNSLRDEDTALYYCARDFP PINLAATTRNYYYYVMDVWGQGTTVTVSS 161 2563  595 FTFSSYSMN 161 2564  596 TTCACCTTCAGTAGCTATAGTATGAAC 161 2565  597 YISSSSSTMYYADSVKG 161 2566  598 TACATTAGTAGTAGTAGTAGTACCATGTACTACGCAGACTCTGTGAAGG GC 161 2567  599 ARDFPPINLAATTRNYYYYVMDV 161 2568  600 GCGAGAGATTTCCCCCCTATTAATCTAGCAGCGACAACCCGAAACTACT ACTACTATGTTATGGACGTC 161 2569  601 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTA AATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTAATCTATG CTACATCCAATTTGAAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATT TTGCAACTTACTACTGTCAACAGAGTTACAGTACCTCGTACACTTTTGGC CAGGGGACCAAAGTGGATATCAAA 161 2570  602 DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPNLLIYATSN LKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTSYTFGQGTKVDI K 161 2571  603 RASQSISSYLN 161 2572  604 CGGGCAAGTCAGAGCATTAGCAGCTATTTAAAT 161 2573  605 ATSNLKS 161 2574  606 GCTACATCCAATTTGAAAAGT 161 2575  607 QQSYSTSYT 161 2576  608 CAACAGAGTTACAGTACCTCGTACACT 162 2577  609 GAGGTGCAGCTGGTGGAGTCCGGCCCTACTCTGGTGAAACCCACACAGA CCCTCACGCTGACCTGCACCTTCTCTGGGTTCTCACTCACCACTATTGGA GTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGGAGTTTC TTGGAATCGTTTATTGGGATGATGATAAGCGGTACAGCCCATCTCTGAA GAGCAGGCTCACCATCACCAAGGACACCTCCAAAAACCAGGTGGTCCTT ACGATGACCACGTTGGCCCCTGAGGACACAGGCACATATTACTGTACAT ACGCCCGCTATAGCAGTGCCTTGTTCGGGGGTTACTACTTTCACTCGTGG GGCCAGGGAACCCTGGTCACCGTCTCCTCA 162 2578  610 EVQLVESGPTLVKPTQTLTLTCTFSGFSLTTIGVGVGWIRQPPGKALEFLGIV YWDDDKRYSPSLKSRLTITKDTSKNQVVLTMTTLAPEDTGTYYCTYARYSS ALFGGYYFHSWGQGTLVTVSS 162 2579  611 FSLTTIGVGVG 162 2580  612 TTCTCACTCACCACTATTGGAGTGGGTGTGGGC 162 2581  613 IVYWDDDKRYSPSLKS 162 2582  614 ATCGTTTATTGGGATGATGATAAGCGGTACAGCCCATCTCTGAAGAGC 162 2583  615 TYARYSSALFGGYYFHS 162 2584  616 ACATACGCCCGCTATAGCAGTGCCTTGTTCGGGGGTTACTACTTTCACTC G 162 2585  617 CAGTCTGTCCTGACGCAGCCGCCCTCGGTGTCAGTGGCCCCAGGACAGA CGGCCAAGATTACCTGTGGGGGAAACGACATTGGAAGTAGAAGTGTGCA CTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTCTATGAT AATAGCGACCGGCCCTCAGGGATCCCTGAACGATTCTCTGGCTCCAATTC TGGAGACACGGCCACCCTGACCATCAGCAGGGTCGAAGCCGGGGATGA GGCCGTCTATTACTGTCAGGTGTGGGAGAGTAGTGGTGATCATCCGAGG ATATTCGGCGGAGGGACCAAGCTCACCGTCCTA 162 2586  618 QSVLTQPPSVSVAPGQTAKITCGGNDIGSRSVHWYQQKPGQAPVLVVYDNS DRPSGIPERFSGSNSGDTATLTISRVEAGDEAVYYCQVWESSGDHPRIFGGG TKLTVL 162 2587  619 GGNDIGSRSVH 162 2588  620 GGGGGAAACGACATTGGAAGTAGAAGTGTGCAC 162 2589  621 DNSDRPS 162 2590  622 GATAATAGCGACCGGCCCTCA 162 2591  623 QVWESSGDHPRI 162 2592  624 CAGGTGTGGGAGAGTAGTGGTGATCATCCGAGGATA 163 2593  625 GAGGTGCAGCTGGTGGAGTCTGGGGGCGCCCTGGTAAAGCCGGGGGGG TCCCTTAGACTCTCCTGTGTAGGCACTGGACTCACTTTCACTACTGCCTA CATGAGCTGGGCCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGT CGTATTCTGAGCAAAAGTGATGGTGGGACAACAGACTACCCTACACCCG TCAAAGGCAGATTCACCATCTCAAGAGATGAATCTAAAAACACCCTGTA TCTGCAAATGAACAGCCTGAAAATCGAGGACACAGCCGTCTATTATTGT ACCACAGATAGGGGGATAACAGCTCGTCCTATCTTCGACTCCTGGGGCC AGGGAACCCTGGTCACCGTCTCCTCA 163 2594  626 EVQLVESGGALVKPGGSLRLSCVGTGLTFTTAYMSWARQAPGKGLEWVGR ILSKSDGGTTDYPTPVKGRFTISRDESKNTLYLQMNSLKIEDTAVYYCTTDR GITARPIFDSWGQGTLVTVSS 163 2595  627 LTFTTAYMS 163 2596  628 CTCACTTTCACTACTGCCTACATGAGC 163 2597  629 RILSKSDGGTTDYPTPVKG 163 2598  630 CGTATTCTGAGCAAAAGTGATGGTGGGACAACAGACTACCCTACACCCG TCAAAGGC 163 2599  631 TTDRGITARPIFDS 163 2600  632 ACCACAGATAGGGGGATAACAGCTCGTCCTATCTTCGACTCC 163 2601  633 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCTAGGGCGGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACATTGGTACAGGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATTTATGGTAACACCAAACGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTATGCCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG ACGATGACGCTGATTATTACTGCCAGTCCTATGACGGCGGCCTGAGTGG TTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA 163 2602  634 QSVLTQPPSVSGALGRRVTISCTGSSSNIGAGYDVHWYRQLPGTAPKLLIYG NTKRPSGVPDRFSGSKYATSASLAITGLQADDDADYYCQSYDGGLSGYVFG TGTKVTVL 163 2603  635 TGSSSNIGAGYDVH 163 2604  636 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAT 163 2605  637 GNTKRPS 163 2606  638 GGTAACACCAAACGGCCCTCA 163 2607  639 QSYDGGLSGYV 163 2608  640 CAGTCCTATGACGGCGGCCTGAGTGGTTATGTC 164 2609  641 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGGCTCTGGATTCACCTTCAGTAGCTATACC CTGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTGAAGGG CCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGCATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTATTGTGCGAGAG CTGACTATGATAGAAGTGTTTATCACCTCAATTGGTTCGACCCCTGGGGC CAGGGAACCCTGGTCACCGTCTCCTCA 164 2610  642 QVQLVQSGGGLVKPGGSLRLSCAGSGFTFSSYTLNWVRQAPGKGLEWVSSI SSSSTYIYYADSVKGRFTISRDNAKNSLHLQMNSLRAEDTAVYYCARADYD RSVYHLNWFDPWGQGTLVTVSS 164 2611  643 FTFSSYTLN 164 2612  644 TTCACCTTCAGTAGCTATACCCTGAAC 164 2613  645 SISSSSTYIYYADSVKG 164 2614  646 TCCATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTGAAGG GC 164 2615  647 ARADYDRSVYHLNWFDP 164 2616  648 GCGAGAGCTGACTATGATAGAAGTGTTTATCACCTCAATTGGTTCGACCC C 164 2617  649 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAACTTCCAGGAGCAGCCCCCAAACTCCTC ATCTATGGTAACACCAATCGGCCCTCAGGGGTCCCTGACCGATTTTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG ACGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGG CACTTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 164 2618  650 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYG NTNRPSGVPDRFSGSKSGTSASLAITGLQADDEADYYCQSYDSSLSGTWVF GGGTKLTVL 164 2619  651 TGSSSNIGAGYDVH 164 2620  652 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 164 2621  653 GNTNRPS 164 2622  654 GGTAACACCAATCGGCCCTCA 164 2623  655 QSYDSSLSGTWV 164 2624  656 CAGTCCTATGACAGCAGCCTGAGTGGCACTTGGGTG 165 2625  657 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGT CCCTGAGACTCTCTTGTTCAGGTTCTGGATTCACCTTTGGGGATTATGCT CTGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTT TCATTAGAAGCAAAGCCTATGGTGGGACAACAGAATACGCCGCGTCTGT GAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTAT CTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTA CTATGGCTGTAGTGGTGCCAGGTGCTACAGATGCTTTTGATATCTGGGGC CAAGGGACAATGGTCACCGTCTCTTCA 165 2626  658 EVQLLESGGGLVQPGRSLRLSCSGSGFTFGDYALSWVRQAPGKGLEWVGFI RSKAYGGTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTMAV VVPGATDAFDIWGQGTMVTVSS 165 2627  659 FTFGDYALS 165 2628  660 TTCACCTTTGGGGATTATGCTCTGAGC 165 2629  661 FIRSKAYGGTTEYAASVKG 165 2630  662 TTCATTAGAAGCAAAGCCTATGGTGGGACAACAGAATACGCCGCGTCTG TGAAAGGC 165 2631  663 TMAVVVPGATDAFDI 165 2632  664 ACTATGGCTGTAGTGGTGCCAGGTGCTACAGATGCTTTTGATATC 165 2633  665 AATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGAC GGTAACCATCTCCTGTACCCGCAGCAGTGGCAGCATTGCCAGCGACTAT GTGCAGTGGTTCCAGCAGCGCCCGGGCAGTTCCCCCGCCACTGTGATCT ATCAGGATAACCAAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGGCTCC ATCGACACCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGAAGAC TGAGGACGAGGCTGACTACTACTGTCACTCTTATGATAGTAGCAATCCTT GGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 165 2634  666 NFMLTQPHSVSESPGKTVTISCTRSSGSIASDYVQWFQQRPGSSPATVIYQDN QRPSGVPDRFSGSIDTSSNSASLTISGLKTEDEADYYCHSYDSSNPWVFGGG TKLTVL 165 2635  667 TRSSGSIASDYVQ 165 2636  668 ACCCGCAGCAGTGGCAGCATTGCCAGCGACTATGTGCAG 165 2637  669 QDNQRPS 165 2638  670 CAGGATAACCAAAGACCCTCT 165 2639  671 HSYDSSNPWV 165 2640  672 CACTCTTATGATAGTAGCAATCCTTGGGTG 166 2641  673 GAGGTGCAGCTGGTGGAGTCCGGAGGAGGCTTGATCCAGCCGGGGGGG TCCCTGAGACTCTCCTGTGCAGTCTCTGGGTTCAGCGTCAGCAGCAACTA TATAAGTTGGGTCCGCCAGCCTCCAGGGAAGGGGCTGGAGTGGGTCTCA GTTAGTTATAGTAGTGGTGTCACAGACTACGCAGACTCCGTGAAGGGCC GATTCACCACCTCCAGAGACAACTCCAAGAACACGCTGTATCTTCAAAT GAACAGCCTGAGAGGCGAAGACACGGCCGTCTATTACTGTGCGAGAGA GTTGGTGCCAAATTTCTATGAAAGTCATGGTTATTTTTCCGTGTGGGGCC AGGGAACCCTGGTCACCGTCTCCTCA 166 2642  674 EVQLVESGGGLIQPGGSLRLSCAVSGFSVSSNYISWVRQPPGKGLEWVSVSY SSGVTDYADSVKGRFTTSRDNSKNTLYLQMNSLRGEDTAVYYCARELVPN FYESHGYFSVWGQGTLVTVSS 166 2643  675 FSVSSNYIS 166 2644  676 TTCAGCGTCAGCAGCAACTATATAAGT 166 2645  677 VSYSSGVTDYADSVKG 166 2646  678 GTTAGTTATAGTAGTGGTGTCACAGACTACGCAGACTCCGTGAAGGGC 166 2647  679 ARELVPNFYESHGYFSV 166 2648  680 GCGAGAGAGTTGGTGCCAAATTTCTATGAAAGTCATGGTTATTTTTCCGT G 166 2649  681 GATATTGTGATGACTCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGAGTTGACAGCAGCTAC TTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGGTGGATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAG TGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGGCTGGAGCCTGAA GATTTTGCGTTGTATTACTGTCAGCAGTATGGTTTCTCACAGACGTTCGG CCAAGGGACCAAGGTGGAGATCAAA 166 2650  682 DIVMTQSPGTLSLSPGERATLSCRASQRVDSSYLAWYQQKPGQAPRLLIYGG SSRATGIPDRFSGSGSGTDFTLTISRLEPEDFALYYCQQYGFSQTFGQGTKVEI K 166 2651  683 RASQRVDSSYLA 166 2652  684 AGGGCCAGTCAGAGAGTTGACAGCAGCTACTTAGCC 166 2653  685 GGSSRAT 166 2654  686 GGTGGATCCAGCAGGGCCACT 166 2655  687 QQYGFSQT 166 2656  688 CAGCAGTATGGTTTCTCACAGACG 167 2657  689 GAGGTGCAGCTGTTGGAGACTGGGGGAGGCTTGGTTAAGCCGGGGGGGT CCCTGAGACTCTCCTGTGAAGCCACTGGATTCACTTTCAGCGACTTTGCC ATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAC TGATTAAAAGTAGTGATTATCCATACTATGCAGACTCCGTGAGGGGCCG CTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCGAATG GACAACCTGAGAGCCGACGACACGGCCGTGTATTACTGTGCCAAGGACG CCGATTTTTGGAGTGGTGAGGCCTACAATGGAGGGTACAACTTTGACTC CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 167 2658  690 EVQLLETGGGLVKPGGSLRLSCEATGFTFSDFAMSWVRQAPGKGLEWVSLI KSSDYPYYADSVRGRFTISRDNSKNTLYLRMDNLRADDTAVYYCAKDADF WSGEAYNGGYNFDSWGQGTLVTVSS 167 2659  691 FTFSDFAMS 167 2660  692 TTCACTTTCAGCGACTTTGCCATGAGC 167 2661  693 LIKSSDYPYYADSVRG 167 2662  694 CTGATTAAAAGTAGTGATTATCCATACTATGCAGACTCCGTGAGGGGC 167 2663  695 AKDADFWSGEAYNGGYNFDS 167 2664  696 GCCAAGGACGCCGATTTTTGGAGTGGTGAGGCCTACAATGGAGGGTACA ACTTTGACTCC 167 2665  697 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTGTCTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTGGCACCAACTTG GCCTGGTACCAGCAAAAACCTGGCCAGGCTCCCCGGCTCCTCATCTTTGG TGCCTCAACCAGGGCCACGGGTATCCCAGCCAGGTTCACTGGCAGTGGG TCTGGGACAGAGTTCACTCTCACCATCGGCAGCCTCCAGTCTGAAGATTT TGCAGTTTATTACTGTCAGCAGTACAATCAGTGGCCTCCGATCACTTTCG GCGGAGGGACCAAGGTGGAAATCAAA 167 2666  698 EIVLTQSPATLSVSPGERATLSCRASQSIGTNLAWYQQKPGQAPRLLIFGAST RATGIPARFTGSGSGTEFTLTIGSLQSEDFAVYYCQQYNQWPPITFGGGTKV EIK 167 2667  699 RASQSIGTNLA 167 2668  700 AGGGCCAGTCAGAGTATTGGCACCAACTTGGCC 167 2669  701 GASTRAT 167 2670  702 GGTGCCTCAACCAGGGCCACG 167 2671  703 QQYNQWPPIT 167 2672  704 CAGCAGTACAATCAGTGGCCTCCGATCACT 168 2673  705 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAAGT CCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCGGTGACTATGGC ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG TTATATCAGATGGTGGAAGCACTAAATACTATGCAGACTCCGTGAAGGG CCGATTCACCATCGCCAGAGACAATTCCAAGAACACGCTGAATCTGCAA ATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAAAG ATTTGGCTTGGATTTTTGGACTGGGTGCTTCATATATGGACGTCTGGGGC CAAGGGACCCTGGTCACCGTCTCCTCA 168 2674  706 EVQLLESGGGVVQPGKSLRLSCVASGFTFGDYGMHWVRQAPGKGLEWVA VISDGGSTKYYADSVKGRFTIARDNSKNTLNLQMNSLRAEDTAVYYCAKD LAWIFGLGASYMDVWGQGTLVTVSS 168 2675  707 FTFGDYGMH 168 2676  708 TTCACCTTCGGTGACTATGGCATGCAC 168 2677  709 VISDGGSTKYYADSVKG 168 2678  710 GTTATATCAGATGGTGGAAGCACTAAATACTATGCAGACTCCGTGAAGG GC 168 2679  711 AKDLAWIFGLGASYMDV 168 2680  712 GCGAAAGATTTGGCTTGGATTTTTGGACTGGGTGCTTCATATATGGACGT C 168 2681  713 GACATCCAGTTGACCCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTGTTAGTAGCAGCTAC TTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGATGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAG TGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAA GATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACCTTTCGGGCT CACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 168 2682  714 DIQLTQSPGTLSLSPGERATLSCRASQTVSSSYLAWYQQKPGQAPRLLIYDA SSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPFGLTFGGGT KVEIK 168 2683  715 RASQTVSSSYLA 168 2684  716 AGGGCCAGTCAGACTGTTAGTAGCAGCTACTTAGCC 168 2685  717 DASSRAT 168 2686  718 GATGCATCCAGCAGGGCCACT 168 2687  719 QQYGSSPFGLT 168 2688  720 CAGCAGTATGGTAGCTCACCTTTCGGGCTCACT 169 2689  721 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGT CCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGGGAGACATGCC ATGACGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGCA GGCATTACTGCTACTGGGGACCCCACATACTACCCAGACTCCGTGAAGG GCCGGTTCGCCGTCTCCAGAGACAACTCCCGGAACACGCTTTATCTGCA AATGGACAGTCTGAGAGTCGAGGACACGGCCCTATATTACTGTGCGAGA AGTTGGGATGACTACGGTGACCTGGACTGGTACTTCGCTCTCTGGGGCC GTGGCACAATGGTCACCGTCTCTTCA 169 2690  722 QVQLVQSGGGLVQPGGSLRLSCAASGFTFGRHAMTWVRQAPGKGLEWVA GITATGDPTYYPDSVKGRFAVSRDNSRNTLYLQMDSLRVEDTALYYCARS WDDYGDLDWYFALWGRGTMVTVSS 169 2691  723 FTFGRHAMT 169 2692  724 TTCACCTTTGGGAGACATGCCATGACG 169 2693  725 GITATGDPTYYPDSVKG 169 2694  726 GGCATTACTGCTACTGGGGACCCCACATACTACCCAGACTCCGTGAAGG GC 169 2695  727 ARSWDDYGDLDWYFAL 169 2696  728 GCGAGAAGTTGGGATGACTACGGTGACCTGGACTGGTACTTCGCTCTC 169 2697  729 GAAATTGTGATGACACAGTCTCCAGCCATCCTGTCTGTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTTG GCCTGGTACCAGCAGAAACCTGGCCAGGCTCCTAGGCTCCTCATCTACG GTGCATCCACCAGGGCCACTGGTATCCCACCCCGGTTCAGTGGCAGTGG GTCTGGGACACAATTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGAT GTTGCAGTATATTACTGTCAGCAGTATAGTGACTGGCCTCCGCTCACTTT CGGCGGGGGGACCAAGGTGGAAATCAAA 169 2698  730 EIVMTQSPAILSVSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYGAST RATGIPPRFSGSGSGTQFTLTISSLQSEDVAVYYCQQYSDWPPLTFGGGTKV EIK 169 2699  731 RASQSVSSSLA 169 2700  732 AGGGCCAGTCAGAGTGTTAGCAGCAGCTTGGCC 169 2701  733 GASTRAT 169 2702  734 GGTGCATCCACCAGGGCCACT 169 2703  735 QQYSDWPPLT 169 2704  736 CAGCAGTATAGTGACTGGCCTCCGCTCACT 170 2705  737 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGT CCCTGAGACTCTCCTGTGGAGCCTCTGGATTCAAGTTCAGTGACTACTAC ATGAGTTGGATCCGCCAGGCTCCAGGGAAGGGGCTAGAGTGGGTTTCAC ACATTAGTAGTAGTAATAGTTACATAAACTACGCAGACTCTGTGAAGGG CCGATTCACCATCTCCAGGGACAACGCCAGGAACTCACTGTCTCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAT TCCCCCTTTACTGTAGTCGTTCCTCCTGCTCCCATTACGTTGACTACTGGG GCCAGGGAACCCTGGTCACCGTCTCCTCA 170 2706  738 EVQLLESGGGLVKPGGSLRLSCGASGFKFSDYYMSWIRQAPGKGLEWVSHI SSSNSYINYADSVKGRFTISRDNARNSLSLQMNSLRAEDTAVYYCARFPLYC SRSSCSHYVDYWGQGTLVTVSS 170 2707  739 FKFSDYYMS 170 2708  740 TTCAAGTTCAGTGACTACTACATGAGT 170 2709  741 HISSSNSYINYADSVKG 170 2710  742 CACATTAGTAGTAGTAATAGTTACATAAACTACGCAGACTCTGTGAAGG GC 170 2711  743 ARFPLYCSRSSCSHYVDY 170 2712  744 GCGAGATTCCCCCTTTACTGTAGTCGTTCCTCCTGCTCCCATTACGTTGAC TAC 170 2713  745 CAGTCTGTCCTGACTCAGCCTCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCGGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGATAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGTTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGGAGCCTGAGTGT GGTATTCGGCGGAGGGACCAAGGTCACCGTCCTA 170 2714  746 QSVLTQPPSVSGAPGQRVTISCTGSGSNIGAGYDVHWYQQLPGTAPKWYD NNNRPSGVPDRFSGSKSGTSASLAITGLQVEDEADYYCQSYDRSLSVVFGG GTKVTVL 170 2715  747 TGSGSNIGAGYDVH 170 2716  748 ACTGGGAGCGGCTCCAACATCGGGGCAGGTTATGATGTACAC 170 2717  749 DNNNRPS 170 2718  750 GATAACAACAATCGGCCCTCA 170 2719  751 QSYDRSLSVV 170 2720  752 CAGTCCTATGACAGGAGCCTGAGTGTGGTA 171 2721  753 CAGGTGCAGCTGGTGCAATCTGGACCAGAGGTGAAAAAGCCCGGGGAG TCTCTGAAGATCTCCTGTAAGGGTTCTGGATATACGTTTACTACCTACTG GATCGGCTGGGTGCGCCAGAGGCCCGGGAAGGGCCTGGAGTGGATGGG AATCATCCATCCCGGTGACTCTGATACCAGATACAGTCCGTCCTTACAAG GCCAGGTCACCATCTCAGTCGACAAGTCCATCAATACCGCCTACCTGCA GTGGAGGAGTTTGAAGGCCTCGGACACCGGCATGTATTATTGTGCGAGA TTCGAATACGGTGACTTCGGGAATGACTTCTGGGGCCAGGGAACCCTGG TCACTGTCTCCTCA 171 2722  754 QVQLVQSGPEVKKPGESLKISCKGSGYTFTTYWIGWVRQRPGKGLEWMGII HPGDSDTRYSPSLQGQVTISVDKSINTAYLQWRSLKASDTGMYYCARFEYG DFGNDFWGQGTLVTVSS 171 2723  755 YTFTTYWIG 171 2724  756 TATACGTTTACTACCTACTGGATCGGC 171 2725  757 IIHPGDSDTRYSPSLQG 171 2726  758 ATCATCCATCCCGGTGACTCTGATACCAGATACAGTCCGTCCTTACAAGG C 171 2727  759 ARFEYGDFGNDF 171 2728  760 GCGAGATTCGAATACGGTGACTTCGGGAATGACTTC 171 2729  761 AATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGAC GGTAACCATCTCCTGCTCCCGCAGCAGTGGCAGCATTGCCAACAACTAT GTGCAGTGGTACCAGCAGCGCCCGGGCAGTTCCCCCACCACTGTGATCT ATGAGGATAACCAAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGGCTCC ATCGACAGCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGAAGAC TGAGGACGAGGCAGACTACTACTGTCAGTCTTATGATAGTAGCAATCAT AGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 171 2730  762 NFMLTQPHSVSESPGKTVTISCSRSSGSIANNYVQWYQQRPGSSPTTVIYEDN QRPSGVPDRFSGSIDSSSNSASLTISGLKTEDEADYYCQSYDSSNHRVFGGGT KLTVL 171 2731  763 SRSSGSIANNYVQ 171 2732  764 TCCCGCAGCAGTGGCAGCATTGCCAACAACTATGTGCAG 171 2733  765 EDNQRPS 171 2734  766 GAGGATAACCAAAGACCCTCT 171 2735  767 QSYDSSNHRV 171 2736  768 CAGTCTTATGATAGTAGCAATCATAGGGTG 172 2737  769 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT CCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGGAGATATGCC ATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAG CTATTACTGCTACTGGTGATACCACATACTACCCAGACTCCGTAAAGGGC CGGTTCGCCGTCTCCAGAGACAATTCCCGGAACACGCTTTATCTGCAAAT GGACAGTCTGAGAGCCGAGGACACGGCCCTATATTACTGTGCGAAAAGT TGGGATGACTACGGTGACCTGGACTGGTACTTCGCTCTCTGGGGCCGTG GCACCCTGGTCACCGTCTCCTCA 172 2738  770 EVQLLESGGGLVQPGGSLRLSCAASGFTFRRYAMTWVRQAPGKGLEWVAA ITATGDTTYYPDSVKGRFAVSRDNSRNTLYLQMDSLRAEDTALYYCAKSW DDYGDLDWYFALWGRGTLVTVSS 172 2739  771 FTFRRYAMT 172 2740  772 TTCACCTTTAGGAGATATGCCATGACC 172 2741  773 AITATGDTTYYPDSVKG 172 2742  774 GCTATTACTGCTACTGGTGATACCACATACTACCCAGACTCCGTAAAGG GC 172 2743  775 AKSWDDYGDLDWYFAL 172 2744  776 GCGAAAAGTTGGGATGACTACGGTGACCTGGACTGGTACTTCGCTCTC 172 2745  777 GATATTGTGATGACCCAGTCTCCAGCCATCCTGTCTGTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTTG GCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTACG GTGCATCCACCAGGGCCACTGGTATCCCACCCCGGTTCAGTGGCAGTGG GTCTGGGACACAATTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATT TTGCAGTGTATTACTGTCAGCAGTATAGTGACTGGCCTCCGCTCACTTTC GGCGGGGGGACCAAGGTGGAGATCAAA 172 2746  778 DIVMTQSPAILSVSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYGAST RATGIPPRFSGSGSGTQFTLTISSLQSEDFAVYYCQQYSDWPPLTFGGGTKVE IK 172 2747  779 RASQSVSSSLA 172 2748  780 AGGGCCAGTCAGAGTGTTAGCAGCAGCTTGGCC 172 2749  781 GASTRAT 172 2750  782 GGTGCATCCACCAGGGCCACT 172 2751  783 QQYSDWPPLT 172 2752  784 CAGCAGTATAGTGACTGGCCTCCGCTCACT 173 2753  785 CAGGTCCAGCTTGTACAGTCTGGGGGAGGTTTGGTACAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTAGATTCACCTTTAGCAGCTATGCC ATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAA CTATTAGTGGTAGTGGTATTAGCACGTACTACGCAGACTCCGTGAAGGG CCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAA ATGAACAGCCTGAGCGCCGAGGACACGGCCGTATATTACTGTGCGAAAG AATTGAGGGAGTATTACTATGATAGCAGTGGCTTTGACTACTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 173 2754  786 QVQLVQSGGGLVQPGGSLRLSCAASRFTFSSYAMSWVRQAPGKGLEWVSTI SGSGISTYYADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAVYYCAKELRE YYYDSSGFDYWGQGTLVTVSS 173 2755  787 FTFSSYAMS 173 2756  788 TTCACCTTTAGCAGCTATGCCATGAGC 173 2757  789 TISGSGISTYYADSVKG 173 2758  790 ACTATTAGTGGTAGTGGTATTAGCACGTACTACGCAGACTCCGTGAAGG GC 173 2759  791 AKELREYYYDSSGFDY 173 2760  792 GCGAAAGAATTGAGGGAGTATTACTATGATAGCAGTGGCTTTGACTAC 173 2761  793 CAGCCTGTGCTGACTCAGTCTCGCTCAGTGTCCGGGTCTCCTGAACAGTC AGTCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAACT ATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGAT TTATGATGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA GGATGAGTCTGATTATTACTGCTGCTCATATGCAGGCACCTACACTTATG TCTTCGGAACTGGGACCAAGGTCACCGTCCTA 173 2762  794 QPVLTQSRSVSGSPEQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIY DVSKRPSGVPDRFSGSKSGNTASLTISGLQAEDESDYYCCSYAGTYTYVFGT GTKVTVL 173 2763  795 TGTSSDVGGYNYVS 173 2764  796 ACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATGTCTCC 173 2765  797 DVSKRPS 173 2766  798 GATGTCAGTAAGCGGCCCTCA 173 2767  799 CSYAGTYTYV 173 2768  800 TGCTCATATGCAGGCACCTACACTTATGTC 174 2769  801 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAAACTCTCCTGTGCAGCCTCTGGATTCAGCTTCACTACCGATGTT ATGCACTGGATACGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GTTATTTCAACTGATGGAGCCAATTCATACTACGCAGAGTCCGTGAAGG GCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTTTCTGCA GATGAGCAGCCTGAGAGCTGAGGACACGGCTGTGTATTATTGTGCGAGC CAGGGATATCATTATGTTAATATGGCTGATGTGGGAGTGCCCTCGTTTGA CCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 174 2770  802 EVQLLESGGGVVQPGRSLKLSCAASGFSFTTDVMHWIRQAPGKGLEWVAVI STDGANSYYAESVKGRFTISRDNSKNTLFLQMSSLRAEDTAVYYCASQGYH YVNMADVGVPSFDHWGQGTLVTVSS 174 2771  803 FSFTTDVMH 174 2772  804 TTCAGCTTCACTACCGATGTTATGCAC 174 2773  805 VISTDGANSYYAESVKG 174 2774  806 GTTATTTCAACTGATGGAGCCAATTCATACTACGCAGAGTCCGTGAAGG GC 174 2775  807 ASQGYHYVNMADVGVPSFDH 174 2776  808 GCGAGCCAGGGATATCATTATGTTAATATGGCTGATGTGGGAGTGCCCT CGTTTGACCAC 174 2777  809 GAAACGACACTCACGCAGTCTCCATCCTCCCTGTCTGCATCTGTCGGAGA CAGAGTCACCATCACTTGCCGGGCACGTCGGAGCATTGACAACTATTTA AATTGGTATCAGCACAAACCAGGGACAGCCCCTAAGCTCCTGATCTATG CTGTATCCAGTTTGCCTAGCGGGGTCCCATCGAGATTCAGTGGCAGTGG ATCTGGGGCAGACTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGAT CTTGCAACTTACTACTGTCAACAGAGTTACATGACCCCTCCCACTTTTGG CCAGGGGACCAAGCTGGAGATCAAA 174 2778  810 ETTLTQSPSSLSASVGDRVTITCRARRSIDNYLNWYQHKPGTAPKLLIYAVSS LPSGVPSRFSGSGSGADFTLTISSLQPEDLATYYCQQSYMTPPTFGQGTKLEI K 174 2779  811 RARRSIDNYLN 174 2780  812 CGGGCACGTCGGAGCATTGACAACTATTTAAAT 174 2781  813 AVSSLPS 174 2782  814 GCTGTATCCAGTTTGCCTAGC 174 2783  815 QQSYMTPPT 174 2784  816 CAACAGAGTTACATGACCCCTCCCACT 175 2785  817 GAGGTGCAGCTGTTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGCGGCACCTTCAGCAGCTATGCT ATAACCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGAG GGATCATCCCTATCCTTGGAACAACAACCTACGCACAGAGGTTCCAGGG CAGAGTCACGATTACCGCGGACAAATCCACGACAACAGCCTACATGGAG CTGAGTCGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTGCGAAAA CGGTGTCACAATATCCCAACACCTACAACTACGGCATGGACGTCTGGGG CCAAGGGACCACGGTCACCGTCTCCTCA 175 2786  818 EVQLLESGAEVKKPGSSVKVSCKASGGTFSSYAITWVRQAPGQGLEWMGGI IPILGTTTYAQRFQGRVTITADKSTTTAYMELSRLRSEDTAVYYCAKTVSQY PNTYNYGMDVWGQGTTVTVSS 175 2787  819 GTFSSYAIT 175 2788  820 GGCACCTTCAGCAGCTATGCTATAACC 175 2789  821 GIIPILGTTTYAQRFQG 175 2790  822 GGGATCATCCCTATCCTTGGAACAACAACCTACGCACAGAGGTTCCAGG GC 175 2791  823 AKTVSQYPNTYNYGMDV 175 2792  824 GCGAAAACGGTGTCACAATATCCCAACACCTACAACTACGGCATGGACG TC 175 2793  825 GAAATTGTGATGACACAGTCTCCCTCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCGTTAGCATCTATTTA AACTGGTATCAGCAGAAACCAGGGAAAACCCCTGAGCTCCTGATCTATG GTGCATCCCGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATT TTGCAACTTACTACTGTCTACAGACGTACTCTACCCCCCTCACCTTCGGC CAAGGGACCAAGGTGGAAATCAAA 175 2794  826 EIVMTQSPSSLSASVGDRVTITCRASQSVSIYLNWYQQKPGKTPELLIYGASR LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQTYSTPLTFGQGTKVEIK 175 2795  827 RASQSVSIYLN 175 2796  828 CGGGCAAGTCAGAGCGTTAGCATCTATTTAAAC 175 2797  829 GASRLQS 175 2798  830 GGTGCATCCCGTTTGCAAAGT 175 2799  831 LQTYSTPLT 175 2800  832 CTACAGACGTACTCTACCCCCCTCACC 176 2801  833 CAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCGGCAGGGATTC TATCAGCTGGGTGCGACAGGCCCCTGGGCAGGGCCTTGAGTGGATGGGA GGGATCAACCCTATCTTTCATACATCACACTACGCACAGAAATTCCAGG GCAGAGTCACAATTACCGCGGACGAGTCCACGAGCACAGCCTACATGGA ACTGGGCAACCTGAGATCTGAGGACACGGCCATGTATTACTGTGCGAGA GTTCCCCCCCCCCGGGGTCATTGTGAGAGTACCAGCTGTTTATGGGGGAC CTATTTTGCCTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 176 2802  834 QVQLVESGAEVKKPGSSVKVSCKASGGTFGRDSISWVRQAPGQGLEWMGG INPIFHTSHYAQKFQGRVTITADESTSTAYMELGNLRSEDTAMYYCARVPPP RGHCESTSCLWGTYFAFWGQGTLVTVSS 176 2803  835 GTFGRDSIS 176 2804  836 GGCACCTTCGGCAGGGATTCTATCAGC 176 2805  837 GINPIFHTSHYAQKFQG 176 2806  838 GGGATCAACCCTATCTTTCATACATCACACTACGCACAGAAATTCCAGG GC 176 2807  839 ARVPPPRGHCESTSCLWGTYFAF 176 2808  840 GCGAGAGTTCCCCCCCCCCGGGGTCATTGTGAGAGTACCAGCTGTTTATG GGGGACCTATTTTGCCTTC 176 2809  841 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGGGTTCGCAGCTACTT AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GATGCATCCATCAGGGCTACTGGCATCCCAGCCAGGTTCAGTGGCAGTG GGTCTGGGGCAGACTTCACTCTCACCATCAGCAGCCTCGAGCCTGAAGA TTTTGCAGTTTATTACTGTCAGCTGCGTGACTACTGGCCTCCCACGTGGA CGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 176 2810  842 ETTLTQSPATLSLSPGERATLSCRASQRVRSYLAWYQQKPGQAPRLLIYDAS IRATGIPARFSGSGSGADFTLTISSLEPEDFAVYYCQLRDYWPPTWTFGQGTK VEIK 176 2811  843 RASQRVRSYLA 176 2812  844 AGGGCCAGTCAGAGGGTTCGCAGCTACTTAGCC 176 2813  845 DASIRAT 176 2814  846 GATGCATCCATCAGGGCTACT 176 2815  847 QLRDYWPPTWT 176 2816  848 CAGCTGCGTGACTACTGGCCTCCCACGTGGACG 177 2817  849 GAGGTGCAGCTGTTGGAGTCTGGGGGAGACCTGGTACAGCCGGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCCCCTTCAGCAGCCATAGC ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGCCTGGAGTGGATCTCAT ACATTAGTGGTGGTAGTGATACCATTCAGTACGCAGACTCTGTGAAGGG CCGATTTACCATCTCCAGAGACAATGTCAAGAATTCACTGTATCTGCAAA TGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGA CCAGTATATTTGGAACTATGTGGAACCTCTTGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 177 2818  850 EVQLLESGGDLVQPGGSLRLSCAASGFPFSSHSMNWVRQAPGKGLEWISYIS GGSDTIQYADSVKGRFTISRDNVKNSLYLQMNSLRAEDTAVYYCARDQYI WNYVEPLDYWGQGTLVTVSS 177 2819  851 FPFSSHSMN 177 2820  852 TTCCCCTTCAGCAGCCATAGCATGAAC 177 2821  853 YISGGSDTIQYADSVKG 177 2822  854 TACATTAGTGGTGGTAGTGATACCATTCAGTACGCAGACTCTGTGAAGG GC 177 2823  855 ARDQYIWNYVEPLDY 177 2824  856 GCGAGAGACCAGTATATTTGGAACTATGTGGAACCTCTTGACTAC 177 2825  857 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGCTATTATTTA GGCTGGTATCAGCAGAAAGCAGGGAAAGCCCCGAAGCTCCTGATTTATG CTGTATCCAATTTGCAAACTGGGGTCCCATCAAGGTTCAGCGGCAGTGG ATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATT TCGCAACTTATTATTGTCTACAAGATCACACTTGCCCTTGGACGTTCGGC CAAGGGACCAAGGTGGAAATCAAA 177 2826  858 DIQMTQSPSSLSASVGDRVTITCRASQDISYYLGWYQQKAGKAPKLLIYAVS NLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQDHTCPWTFGQGTKV EIK 177 2827  859 RASQDISYYLG 177 2828  860 CGGGCAAGTCAGGACATTAGCTATTATTTAGGC 177 2829  861 AVSNLQT 177 2830  862 GCTGTATCCAATTTGCAAACT 177 2831  863 LQDHTCPWT 177 2832  864 CTACAAGATCACACTTGCCCTTGGACG 178 2833  865 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAAGTCTCCTGCAAGGTTTCTGGAGGCACCTTCAGCACTTATGGT ATCAGCTGGATACAACAGGCCCCTGGACAAGGGCTTGAGTGGGTGGGAG GGATCATCCCTATGTTTGGGACAGCAAACTACGCACAGAGGTTTCAGGG CAGAGTCACCCTTACCGCGGACGAAGGCACGAACACAGCTTACATGGAG CTGAACAACCTGAGATCTGAGGACACGGCCATGTATTACTGTGCGAGAG ATCGAGGTAATAACGGCCGCTACTACGCTATGGACGTCTGGGGCCAGGG GACCACGGTCACCGTCTCCTCA 178 2834  866 EVQLVESGAEVKKPGSSVKVSCKVSGGTFSTYGISWIQQAPGQGLEWVGGII PMFGTANYAQRFQGRVTLTADEGTNTAYMELNNLRSEDTAMYYCARDRG NNGRYYAMDVWGQGTTVTVSS 178 2835  867 GTFSTYGIS 178 2836  868 GGCACCTTCAGCACTTATGGTATCAGC 178 2837  869 GIIPMFGTANYAQRFQG 178 2838  870 GGGATCATCCCTATGTTTGGGACAGCAAACTACGCACAGAGGTTTCAGG GC 178 2839  871 ARDRGNNGRYYAMDV 178 2840  872 GCGAGAGATCGAGGTAATAACGGCCGCTACTACGCTATGGACGTC 178 2841  873 GATATTGTGCTGACCCAGACTCCAGCCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTCACCACCTACTTA GCGTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATACATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGCGTAACAACTGGCCGCCGACCTTCGG CCAAGGGACACGACTGGAGATTAAA 178 2842  874 DIVLTQTPATLSLSPGERATLSCRASQSVTTYLAWYQQKPGQAPRLLIYDTS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNNWPPTFGQGTRLE IK 178 2843  875 RASQSVTTYLA 178 2844  876 AGGGCCAGTCAGAGTGTCACCACCTACTTAGCG 178 2845  877 DTSNRAT 178 2846  878 GATACATCCAACAGGGCCACT 178 2847  879 QQRNNWPPT 178 2848  880 CAGCAGCGTAACAACTGGCCGCCGACC 179 2849  881 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCGGGATTCACCATCAGTGGTTATAAC ATGTTCTGGGTCCGCCAGCCTCCGGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGGC CGTTTCATCGTCTCCAGAGACAACGCCAAGAATTCACTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTTCTGTGCGAGAGCA CCTCTTTTACCCGCTATGATGGACCTCTGGGGCCAAGGGACCACGGTCAC CGTCTCCTCA 179 2850  882 EVQLLESGGGLVKPGGSLRLSCAASGFTISGYNMFWVRQPPGKGLEWVSSI TAGSSYLNYADSVKGRFIVSRDNAKNSLYLQMNSLRAEDTAVYFCARAPLL PAMMDLWGQGTTVTVSS 179 2851  883 FTISGYNMF 179 2852  884 TTCACCATCAGTGGTTATAACATGTTC 179 2853  885 SITAGSSYLNYADSVKG 179 2854  886 TCCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGG C 179 2855  887 ARAPLLPAMMDL 179 2856  888 GCGAGAGCACCTCTTTTACCCGCTATGATGGACCTC 179 2857  889 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATCTATACTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCCTGAATGG TTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 179 2858  890 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYT NNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLNGYVFG TGTKLTVL 179 2859  891 TGSSSNIGAGYDVH 179 2860  892 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 179 2861  893 TNNNRPS 179 2862  894 ACTAACAACAATCGGCCCTCA 179 2863  895 QSYDRSLNGYV 179 2864  896 CAGTCCTATGACAGAAGCCTGAATGGTTATGTC 180 2865  897 GAGGTGCAGCTGGTGGAGACTGGGGGAGGCCTGGTCAAGCCTGGGGGG TCCCTGAGACTCTCCTGTGCAGGCTCTGGATTCACCTTCAGTAGCTATAC CCTGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCA TCTATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTGAAGG GCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGCATCTGCA AATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTATTGTGCGAGA GCTGACTATGATAGAAGTGTTTATCACCTCAATTGGCTCGACCCCTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCA 180 2866  898 EVQLVETGGGLVKPGGSLRLSCAGSGFTFSSYTLNWVRQAPGKGLEWVSSI SSSSTYIYYADSVKGRFTISRDNAKNSLHLQMNSLRAEDTAVYYCARADYD RSVYHLNWLDPWGQGTLVTVSS 180 2867  899 FTFSSYTLN 180 2868  900 TTCACCTTCAGTAGCTATACCCTGAAC 180 2869  901 SISSSSTYIYYADSVKG 180 2870  902 TCTATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTGAAGG GC 180 2871  903 ARADYDRSVYHLNWLDP 180 2872  904 GCGAGAGCTGACTATGATAGAAGTGTTTATCACCTCAATTGGCTCGACC CC 180 2873  905 CAGCCTGTGCTGACTCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAACTTCCAGGAGCAGCCCCCAAACTCCTC ATCTATGGTAACACCAATCGGCCCTCAGGGGTCCCTGACCGATTTTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG ACGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGG CACTTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 180 2874  906 QPVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGAAPKLLIYG NTNRPSGVPDRFSGSKSGTSASLAITGLQADDEADYYCQSYDSSLSGTWVF GGGTKLTVL 180 2875  907 TGSSSNIGAGYDVH 180 2876  908 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 180 2877  909 GNTNRPS 180 2878  910 GGTAACACCAATCGGCCCTCA 180 2879  911 QSYDSSLSGTWV 180 2880  912 CAGTCCTATGACAGCAGCCTGAGTGGCACTTGGGTG 181 2881  913 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACCACTAC ATGACCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAT ACATTAGCAGTACTAGTAGTTTCACAAACTACGCAGACTCTGTGAAGGG CCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCACTTTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAG ACCGCAATTGGGGATATGCCTATGGTTCTGACTACTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCA 181 2882  914 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDHYMTWIRQAPGKGLEWVSYI SSTSSFTNYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTAVYYCARDRNW GYAYGSDYWGQGTLVTVSS 181 2883  915 FTFSDHYMT 181 2884  916 TTCACCTTCAGTGACCACTACATGACC 181 2885  917 YISSTSSFTNYADSVKG 181 2886  918 TACATTAGCAGTACTAGTAGTTTCACAAACTACGCAGACTCTGTGAAGG GC 181 2887  919 ARDRNWGYAYGSDY 181 2888  920 GCGAGAGACCGCAATTGGGGATATGCCTATGGTTCTGACTAC 181 2889  921 GACATCCGGTTGACCCAGTCTCCAGACACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCACCTAC TTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATTTA TGGTGCATTCGGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGT GGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAG ATTTTGCAGTGTATTACTGTCAGCTGTATGGTAACTCACGGACGTTCGGC CAAGGGACCAAGCTGGAGATCAAA 181 2890  922 DIRLTQSPDTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQAPRLLIYGAF GRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQLYGNSRTFGQGTKLEI K 181 2891  923 RASQSVSSTYLA 181 2892  924 AGGGCCAGTCAGAGTGTTAGCAGCACCTACTTAGCC 181 2893  925 GAFGRAT 181 2894  926 GGTGCATTCGGCAGGGCCACT 181 2895  927 QLYGNSRT 181 2896  928 CAGCTGTATGGTAACTCACGGACG 182 2897  929 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT CCCTGAGAATCTCCTGTGCAGCCTCTGGATTCTCCATTAGTAGTCATGCC GTGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAG TTATTAGTGGGAGTGGTGGTGACACACACTCCGTAGTTCAAGGTCGTGG TAGTGGCACATATTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCC AGAGACAATGTCAGGAACACAGTGTATCTGCAAATGAATAGCCTGAGGG TCGAGGACACGGCCGTATATTATTGTGCGAAAGACGACCCCACGCTTTTT TGGAGTGGTTCGGGGTACTACGGAATGGACGTCTGGGGCCAAGGGACCA CGGTCACCGTCTCCTCA 182 2898  930 EVQLVESGGGLVQPGGSLRISCAASGFSISSHAVSWVRQAPGKGLEWVSVIS GSGGDTHSVVQGRGSGTYYADSVKGRFTISRDNVRNTVYLQMNSLRVEDT AVYYCAKDDPTLFWSGSGYYGMDVWGQGTTVTVSS 182 2899  931 FSISSHAVS 182 2900  932 TTCTCCATTAGTAGTCATGCCGTGAGC 182 2901  933 VISGSGGDTHSVVQGRGSGTYYADSVKG 182 2902  934 GTTATTAGTGGGAGTGGTGGTGACACACACTCCGTAGTTCAAGGTCGTG GTAGTGGCACATATTACGCAGACTCCGTGAAGGGC 182 2903  935 AKDDPTLFWSGSGYYGMDV 182 2904  936 GCGAAAGACGACCCCACGCTTTTTTGGAGTGGTTCGGGGTACTACGGAA TGGACGTC 182 2905  937 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGAGA CAGAGTCACCATCACTTGCCAGGCGAGTCAGGGCATTAGCGACTCTTTA AATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACG GTGCATCCAAATTGGAACCAGGGGTCTCATCAAGGTTCAGCGGACGAGG ATCTGGGAGAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGAT ATCGGAACATATTACTGTCAACAGTATGATAATCTCCCTCTGACTTTCGG CCCTGGGACCAAGCTGGAGATCAAA 182 2906  938 DIRVTQSPSSLSASVGDRVTITCQASQGISDSLNWYQQKPGKAPKLLIYGAS KLEPGVSSRFSGRGSGRDFTFTISSLQPEDIGTYYCQQYDNLPLTFGPGTKLEI K 182 2907  939 QASQGISDSLN 182 2908  940 CAGGCGAGTCAGGGCATTAGCGACTCTTTAAAT 182 2909  941 GASKLEP 182 2910  942 GGTGCATCCAAATTGGAACCA 182 2911  943 QQYDNLPLT 182 2912  944 CAACAGTATGATAATCTCCCTCTGACT 183 2913  945 GAGGTGCAGCTGGTGGAGACGGGGGGCGGCTTGATACAGCCGGGGGGG TCCCTGAGACTCTCCTGCGTGGCCTCCGGATTCAGCCTTAGGAACTATGC CTTAGGTTGGCTCCGCCAGGCGCCAGGGAAGGGGCTGGAGTGGGTCTCA GGTGGCTATTATGGTGATGTCTATTACACGGACTCCGTGAAGGGCCGGTT CGCCGTCTCCAGGGACAATTCCGGGGACACAGTATATCTAGAAATGGAC AACCTGAGAGTCGAAGACACGGCCGTGTATTACTGTGCGAGAATGGAGA CAGTGACCACTGATGCAGGCTCGGGATGGGACTGGTACTTCGAGGTCTG GGGCCGCGGCACCCTGGTCACTGTCTCCTCA 183 2914  946 EVQLVETGGGLIQPGGSLRLSCVASGFSLRNYALGWLRQAPGKGLEWVSG GYYGDVYYTDSVKGRFAVSRDNSGDTVYLEMDNLRVEDTAVYYCARMET VTTDAGSGWDWYFEVWGRGTLVTVSS 183 2915  947 FSLRNYALG 183 2916  948 TTCAGCCTTAGGAACTATGCCTTAGGT 183 2917  949 GGYYGDVYYTDSVKG 183 2918  950 GGTGGCTATTATGGTGATGTCTATTACACGGACTCCGTGAAGGGC 183 2919  951 ARMETVTTDAGSGWDWYFEV 183 2920  952 GCGAGAATGGAGACAGTGACCACTGATGCAGGCTCGGGATGGGACTGG TACTTCGAGGTC 183 2921  953 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGG ATTGGGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCACCTACTTA GCCTGGTACCAACACAAACCTGGCCAGGCTCCCAGACTCCTCATTCATG ATGCATCCAACAGGGCCAGTGACATCCCATCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCCGCGGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCAACATCGCGACTGGCGGCCGGTCACTTT CGGCGGAGGGACCAAGGTGGAAATCAAA 183 2922  954 ETTLTQSPATLSLSPGDWATLSCRASQSVGTYLAWYQHKPGQAPRLLIHDA SNRASDIPSRFSGSGSGTDFTLTIRGLEPEDFAVYYCQQHRDWRPVTFGGGT KVEIK 183 2923  955 RASQSVGTYLA 183 2924  956 AGGGCCAGTCAGAGTGTTGGCACCTACTTAGCC 183 2925  957 DASNRAS 183 2926  958 GATGCATCCAACAGGGCCAGT 183 2927  959 QQHRDWRPVT 183 2928  960 CAGCAACATCGCGACTGGCGGCCGGTCACT 184 2929  961 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGCGAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCACGGCGTCTGGATACACCTTCACCAATGATATT AACTGGGTGCGCCAGGCCACTGGACAAGGGCTTGAGTGGATGGGGTGG ATGAACCCTAACAACGGTCACACAGGATATGGACAGAAGTTCGAGGAC AGAGTCACCTTGACAAGGGACTCCTCCAGAAGCACAGCCTACATGGAAC TGAGCAGCCTGAGATTTGAGGACACGGCCGTGTACTATTGTGTATACAA TTTTTGGAGCGATTCTTCAGTCAGTTGGGGCCGGGGAACCCTGGTCACCG TCTCCTCA 184 2930  962 QVQLVQSGAEAKKPGASVKVSCTASGYTFTNDINWVRQATGQGLEWMGW MNPNNGHTGYGQKFEDRVTLTRDSSRSTAYMELSSLRFEDTAVYYCVYNF WSDSSVSWGRGTLVTVSS 184 2931  963 YTFTNDIN 184 2932  964 TACACCTTCACCAATGATATTAAC 184 2933  965 WMNPNNGHTGYGQKFED 184 2934  966 TGGATGAACCCTAACAACGGTCACACAGGATATGGACAGAAGTTCGAGG AC 184 2935  967 VYNFWSDSSVS 184 2936  968 GTATACAATTTTTGGAGCGATTCTTCAGTCAGT 184 2937  969 CAGTCTGTCGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GTGTCGCCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGCCAGCCTA TGATGTACACTGGTACCAGCAGACTCCGGGAGCAGCCCCCAAACTCCTC ATCTATGGTGACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTAC CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTTTGACAGCAGCCTGCGTGGT TATGTCTTCGGAACTGGGACCAAGGTGACCGTCCTA 184 2938  970 QSVVTQPPSVSGAPGQSVAISCTGSSSNIGPAYDVHWYQQTPGAAPKLLIYG DSNRPSGVPDRFSTSKSGTSASLAITGLQAEDEADYYCQSFDSSLRGYVFGT GTKVTVL 184 2939  971 TGSSSNIGPAYDVH 184 2940  972 ACTGGGAGCAGCTCCAACATCGGGCCAGCCTATGATGTACAC 184 2941  973 GDSNRPS 184 2942  974 GGTGACAGCAATCGGCCCTCA 184 2943  975 QSFDSSLRGYV 184 2944  976 CAGTCCTTTGACAGCAGCCTGCGTGGTTATGTC 185 2945  977 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCAGTTATGAT ATCAACTGGGTGCGACAGGCCACTGGACATGGGCTTGAGTGGATGGGAT GGATGAGCCCTAACAGTGGTTACACAGGCTATGCACAGAAGTTCCAGGG CAGAGTCACCATGAGCAGGAACACCTCCACAGGCACAGCCTACATGGAG CTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAG AGGCCCGGGACCTACGAGTGGGAGCTACTAACTTTGACTACTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 185 2946  978 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGHGLEWMG WMSPNSGYTGYAQKFQGRVTMSRNTSTGTAYMELSSLRSEDTAVYYCARE ARDLRVGATNFDYWGQGTLVTVSS 185 2947  979 YTFTSYDIN 185 2948  980 TACACCTTCACCAGTTATGATATCAAC 185 2949  981 WMSPNSGYTGYAQKFQG 185 2950  982 TGGATGAGCCCTAACAGTGGTTACACAGGCTATGCACAGAAGTTCCAGG GC 185 2951  983 AREARDLRVGATNFDY 185 2952  984 GCGAGAGAGGCCCGGGACCTACGAGTGGGAGCTACTAACTTTGACTAC 185 2953  985 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAGA CAGCCAGCATAACCTGCTCTGGAGATAAATTGGGAGATAAATATATTTC GTGGTATCAACAGAGGCCAGGCCAGTCCCCTGTAATGGTAATTTATCAA GATAGCAAGGGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACT CTGGGAACACAGCCACTCTGACCATCAGCGGGACGCAGGCTATGGATGA GGCTGACTATTACTGTCAGGCGTGGGACAGCAGCATAGATGTGGTATTC GGCGGAGGGACCAAGCTCACCGTCCTA 185 2954  986 QPVLTQPPSVSVSPGQTASITCSGDKLGDKYISWYQQRPGQSPVMVIYQDSK GPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSSIDVVFGGGTKL TVL 185 2955  987 SGDKLGDKYIS 185 2956  988 TCTGGAGATAAATTGGGAGATAAATATATTTCG 185 2957  989 QDSKGPS 185 2958  990 CAAGATAGCAAGGGGCCCTCA 185 2959  991 QAWDSSIDVV 185 2960  992 CAGGCGTGGGACAGCAGCATAGATGTGGTA 186 2961  993 CAGGTCCAGCTGGTGCAGTCTGGGCCTGAGATGAAGAAGCCTGGGTCCT CCGTGAAGGTCTCCTGCAAGCCTTCTGGAGGCACCTTCAGCAGCTACTCT GTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GAATCATCCCGATATTTGGTTCGTCAGACTACGCACAGAAGTTTCAGGG CAGACTCACAATTACAGAGGACGAATCCACGAAGACATCCTACATGCAG CTGAACAACCTGACATCTGACGACACGGCCATTTATTTCTGTGCGAGAG ACAACTACTATGTTTGGACTGGTCACTATCCCGAATTTGACTTCTGGGGC CAGGGAACCCTGGTCACCGTCTCCTCA 186 2962  994 QVQLVQSGPEMKKPGSSVKVSCKPSGGTFSSYSVSWVRQAPGQGLEWMGG IIPIFGSSDYAQKFQGRLTITEDESTKTSYMQLNNLTSDDTAIYFCARDNYYV WTGHYPEFDFWGQGTLVTVSS 186 2963  995 GTFSSYSVS 186 2964  996 GGCACCTTCAGCAGCTACTCTGTCAGC 186 2965  997 GIIPIFGSSDYAQKFQG 186 2966  998 GGAATCATCCCGATATTTGGTTCGTCAGACTACGCACAGAAGTTTCAGG GC 186 2967  999 ARDNYYVWTGHYPEFDF 186 2968 1000 GCGAGAGACAACTACTATGTTTGGACTGGTCACTATCCCGAATTTGACTT C 186 2969 1001 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCCTTGTCTCTAGGGG AGACTGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTGAGAAGCGATTA CTTAGCCTGGTACCAACAGAAACCAGGCCAGGCTCCCAGGCTCCTCATC TCTGGTGCATCCAACAGGGCCACTGCCATCCCAGAGAGGTTCACTGGCA GTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAGCCTGC AGATTTTGCAGTGTATTATTGTCAGCAGTATGGTAGCACACCGATCACCT TCGGCCAGGGGACACGACTGGAGATTAAA 186 2970 1002 ETTLTQSPGTLSLSLGETATLSCRASQSVRSDYLAWYQQKPGQAPRLLISGA SNRATAIPERFTGSGSGTDFTLTISSLEPADFAVYYCQQYGSTPITFGQGTRLE IK 186 2971 1003 RASQSVRSDYLA 186 2972 1004 AGGGCCAGTCAGAGTGTGAGAAGCGATTACTTAGCC 186 2973 1005 GASNRAT 186 2974 1006 GGTGCATCCAACAGGGCCACT 186 2975 1007 QQYGSTPIT 186 2976 1008 CAGCAGTATGGTAGCACACCGATCACC 187 2977 1009 CAGGTGCAGCTGCAGGAGTCGGGGGGAGGCTTGGTACAGCCTGGGGGG TCCCTGAGACTCTCCTGTTCAGCCTCTGGATTCACCTTTAGTAACTATGG CATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCA GGTATTGGTGTGAGTGATGGAAGCACACACTACGCGGACTCCGTGAAGG GCCGGTTCATCATCTCCAGAGACAATTCCAAGAACATGCTGTCTCTGCAA ATGAGCAGCCTGGGAGTCGACGACACGGCCGTATATTACTGTGCGAGAA TTGTAATTGTTGGAGTATTACGATTTCAGGAGTGGTTATCATCTGACGGG ATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 187 2978 1010 QVQLQESGGGLVQPGGSLRLSCSASGFTFSNYGMSWVRQAPGKGLEWVSG IGVSDGSTHYADSVKGRFIISRDNSKNMLSLQMSSLGVDDTAVYYCARIVIV GVLRFQEWLSSDGMDVWGQGTTVTVSS 187 2979 1011 FTFSNYGMS 187 2980 1012 TTCACCTTTAGTAACTATGGCATGAGT 187 2981 1013 GIGVSDGSTHYADSVKG 187 2982 1014 GGTATTGGTGTGAGTGATGGAAGCACACACTACGCGGACTCCGTGAAGG GC 187 2983 1015 ARIVIVGVLRFQEWLSSDGMDV 187 2984 1016 GCGAGAATTGTAATTGTTGGAGTATTACGATTTCAGGAGTGGTTATCATC TGACGGGATGGACGTC 187 2985 1017 GATATTGTGATGACCCAGACTCCATCTTCCGTGTCTGCATCTGTAGGAGA CAGAGTCACGATCACTTGTCGGGCGAGTCAGGCCATTAGTGGCGGGTTA GCCTGGTATCAGCAGAAAGCAGGAAAAGCCCCTAAACTCCTGATCTATG CTGCATCCAATTTGCCAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAGGATT TTGCGACTTATTATTGTCAACAGGCTAACAGTTTCCCCTTCACCTTCGGC CAAGGGACACGACTGGAGATTAAA 187 2986 1018 DIVMTQTPSSVSASVGDRVTITCRASQAISGGLAWYQQKAGKAPKLLIYAAS NLPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPFTFGQGTRLEI K 187 2987 1019 RASQAISGGLA 187 2988 1020 CGGGCGAGTCAGGCCATTAGTGGCGGGTTAGCC 187 2989 1021 AASNLPS 187 2990 1022 GCTGCATCCAATTTGCCAAGT 187 2991 1023 QQANSFPFT 187 2992 1024 CAACAGGCTAACAGTTTCCCCTTCACC 188 2993 1025 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCGGGATTCACCATCGGTGGTTATAAC ATGTTCTGGGTCCGCCAGCCTCCGGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGGC CGTTTCATCGTCTCCAGAGACAACGCCAAGAATTCACTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTTCTGTGCGAGAGCA CCTCTTTTACCCGCTATGATGGACCTCTGGGGCCAAGGGACCACGGTCAC CGTCTCCTCA 188 2994 1026 EVQLLESGGGLVKPGGSLRLSCAASGFTIGGYNMFWVRQPPGKGLEWVSSI TAGSSYLNYADSVKGRFIVSRDNAKNSLYLQMNSLRAEDTAVYFCARAPLL PAMMDLWGQGTTVTVSS 188 2995 1027 FTIGGYNMF 188 2996 1028 TTCACCATCGGTGGTTATAACATGTTC 188 2997 1029 SITAGSSYLNYADSVKG 188 2998 1030 TCCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGG C 188 2999 1031 ARAPLLPAMMDL 188 3000 1032 GCGAGAGCACCTCTTTTACCCGCTATGATGGACCTC 188 3001 1033 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATCTATACTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCCTGAATGG TTATGTCTTCGGAACTGGCACCCAGCTGACCGTCCTC 188 3002 1034 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYT NNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLNGYVFG TGTQLTVL 188 3003 1035 TGSSSNIGAGYDVH 188 3004 1036 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 188 3005 1037 TNNNRPS 188 3006 1038 ACTAACAACAATCGGCCCTCA 188 3007 1039 QSYDRSLNGYV 188 3008 1040 CAGTCCTATGACAGAAGCCTGAATGGTTATGTC 189 3009 1041 CAGGTCCAGCTTGTACAGTCTGGGGGAGGCTTGGTCAAGGCTGGAGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTGGCTTCTAC ATGACCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAT CCATTAGTGGTAGTAGTAGTTACACAAACTACGCAGACTCTGTGAAGGG CCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAC ATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA TAAGGCCGGATGATAGTAGTGGTTATCCTGACTACTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCA 189 3010 1042 QVQLVQSGGGLVKAGGSLRLSCAASGFTISGFYMTWIRQAPGKGLEWVSSI SGSSSYTNYADSVKGRFTISRDNAKNSLYLHMNSLRAEDTAVYYCARIRPD DSSGYPDYWGQGTLVTVSS 189 3011 1043 FTISGFYMT 189 3012 1044 TTCACCATCAGTGGCTTCTACATGACC 189 3013 1045 SISGSSSYTNYADSVKG 189 3014 1046 TCCATTAGTGGTAGTAGTAGTTACACAAACTACGCAGACTCTGTGAAGG GC 189 3015 1047 ARIRPDDSSGYPDY 189 3016 1048 GCGAGAATAAGGCCGGATGATAGTAGTGGTTATCCTGACTAC 189 3017 1049 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCTGGTTA TGATGTACACTGGTGCCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGG CTTTGTCTTCGGAACTGGGACCAAGGTGACCGTCCTA 189 3018 1050 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWCQQLPGTAPKLLIYG NNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGFVFGT GTKVTVL 189 3019 1051 TGSSSNIGAGYDVH 189 3020 1052 ACTGGGAGCAGCTCCAACATCGGGGCTGGTTATGATGTACAC 189 3021 1053 GNNNRPS 189 3022 1054 GGTAACAACAATCGGCCCTCA 189 3023 1055 QSYDSSLSGFV 189 3024 1056 CAGTCCTATGACAGCAGCCTGAGTGGCTTTGTC 190 3025 1057 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAGGAAGCCTGGGGCCT CAGTGCAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGCTACTAT ATGCACTGGGTGCGACAGGCCCCTGGACACGGGCTTGAGTGGATGGGAA TGATCTACCCTAGTGGTGGTAGCACAAGCTACGCACAGAAGTTCCAGGG CAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGAG CTGAGCAGCCTGAGATCTGAGGACGCGGCCGTGTATTACTGTGCGAGAG ACCGGGCAGGGTGTAGTGGTGGTAGCTGTTACTATTATGGTATGGACGT CTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 190 3026 1058 EVQLVESGAEVRKPGASVQVSCKASGYTFTSYYMHWVRQAPGHGLEWMG MIYPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDAAVYYCARDR AGCSGGSCYYYGMDVWGQGTTVTVSS 190 3027 1059 YTFTSYYMH 190 3028 1060 TACACCTTCACCAGCTACTATATGCAC 190 3029 1061 MIYPSGGSTSYAQKFQG 190 3030 1062 ATGATCTACCCTAGTGGTGGTAGCACAAGCTACGCACAGAAGTTCCAGG GC 190 3031 1063 ARDRAGCSGGSCYYYGMDV 190 3032 1064 GCGAGAGACCGGGCAGGGTGTAGTGGTGGTAGCTGTTACTATTATGGTA TGGACGTC 190 3033 1065 AATTTTATGCTGACTCAGCCCCCCTCAGTGTCCGTGTCCCCAGGACAGAC AGCCAGCATCACCTGCTCTGGAAATAAATTGGGGGATAAATATGCTTGC TGGTATCAACAAAAGCCAGGCCAGTCCCCTGTGCTGGTCATCTCTCAAG ATAGCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCT GGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATGGATGAGG CTGACTATTACTGTCAGGCGTGGGACAGTAGAACTGTTGTATTCGGCGG AGGGACCAAGCTGACCGTCCTA 190 3034 1066 NFMLTQPPSVSVSPGQTASITCSGNKLGDKYACWYQQKPGQSPVLVISQDS KRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSRTVVFGGGTK LTVL 190 3035 1067 SGNKLGDKYAC 190 3036 1068 TCTGGAAATAAATTGGGGGATAAATATGCTTGC 190 3037 1069 QDSKRPS 190 3038 1070 CAAGATAGCAAGCGGCCCTCA 190 3039 1071 QAWDSRTVV 190 3040 1072 CAGGCGTGGGACAGTAGAACTGTTGTA 191 3041 1073 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGTAGTTATGA AATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGA GGGATCAACCCTATGTTTGGAGCAGCAAACTACGCACAGAAGTTCCAGG ACAGAGTCACGATTATCGCGGACAAATCCACGGGCACAGTCTACATGGA ACTGAGCAGCCTGAGATCTGAGGACACGGCCCTCTATTACTGTGCGAGA GAACGCTACCCGTCTACGGATGACTATTATAGGAGTGGTCGTTACTACG GGGAGTGGGGCCAGGGGACCACGGTCACCGTCTCCTCA 191 3042 1074 EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYEISWVRQAPGQGLEWMGGI NPMFGAANYAQKFQDRVTIIADKSTGTVYMELSSLRSEDTALYYCARERYP STDDYYRSGRYYGEWGQGTTVTVSS 191 3043 1075 GTFSSYEIS 191 3044 1076 GGCACCTTCAGTAGTTATGAAATCAGC 191 3045 1077 GINPMFGAANYAQKFQD 191 3046 1078 GGGATCAACCCTATGTTTGGAGCAGCAAACTACGCACAGAAGTTCCAGG AC 191 3047 1079 ARERYPSTDDYYRSGRYYGE 191 3048 1080 GCGAGAGAACGCTACCCGTCTACGGATGACTATTATAGGAGTGGTCGTT ACTACGGGGAG 191 3049 1081 GAAACGACACTCACGCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTCGTAGTTGGTTG GCCTGGTATCAGCAGAAACCAGGGAAAGCCCCGAAGCTCCTGATCTATA GGGCGTCTACTTCAGACAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGG ATCTGGGACAGAATTCACGCTCACCATCAGCAGCCTGCAGCCTGATGAT TTTGCAATTTATTACTGCCAACAGTATAATAGCATCCCAGTGACGTTCGG CCAAGGGACCAAGCTGGAGATCAAA 191 3050 1082 ETTLTQSPSTLSASVGDRVTITCRASQSIRSWLAWYQQKPGKAPKLLIYRAS TSDSGVPSRFSGSGSGTEFTLTISSLQPDDFAIYYCQQYNSIPVTFGQGTKLEI K 191 3051 1083 RASQSIRSWLA 191 3052 1084 CGGGCCAGTCAGAGTATTCGTAGTTGGTTGGCC 191 3053 1085 RASTSDS 191 3054 1086 AGGGCGTCTACTTCAGACAGT 191 3055 1087 QQYNSIPVT 191 3056 1088 CAACAGTATAATAGCATCCCAGTGACG 192 3057 1089 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACATTCAGTGACTATGCC ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG TTATATGGTATGATGGAGGTAATAAATACTATGCAGACTCCGCGAAGGG CCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAAAG ATCGCGGGTCTATCTGGAACGTTGGGGATGGTATGGACGTCTGGGGCCA AGGGACCACGGTCACCGTCTCTTCA 192 3058 1090 EVQLVESGGGVVQPGRSLRLSCAASGFTFSDYAMHWVRQAPGKGLEWVA VIWYDGGNKYYADSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD RGSIWNVGDGMDVWGQGTTVTVSS 192 3059 1091 FTFSDYAMH 192 3060 1092 TTCACATTCAGTGACTATGCCATGCAC 192 3061 1093 VIWYDGGNKYYADSAKG 192 3062 1094 GTTATATGGTATGATGGAGGTAATAAATACTATGCAGACTCCGCGAAGG GC 192 3063 1095 AKDRGSIWNVGDGMDV 192 3064 1096 GCGAAAGATCGCGGGTCTATCTGGAACGTTGGGGATGGTATGGACGTC 192 3065 1097 CAGCCTGTGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGA CGGCCAGGGTTACCTGTGGGGGAAACAACATTGGAGCTAAGAGTGTCCA CTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTCGATGAT GATACCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTC TGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAGCCGGGGATGA GGCCGACTATTACTGTCAGGTGTGGGATGCTAGTATTGGTCCTCTTTATG TCTTCGGAACTGGGACCAAGCTCACCGTCCTA 192 3066 1098 QPVLTQPPSVSVAPGQTARVTCGGNNIGAKSVHWYQQKPGQAPVLVVDDD TDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDASIGPLYVFGT GTKLTVL 192 3067 1099 GGNNIGAKSVH 192 3068 1100 GGGGGAAACAACATTGGAGCTAAGAGTGTCCAC 192 3069 1101 DDTDRPS 192 3070 1102 GATGATACCGACCGGCCCTCA 192 3071 1103 QVWDASIGPLYV 192 3072 1104 CAGGTGTGGGATGCTAGTATTGGTCCTCTTTATGTC 193 3073 1105 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGTTTCACCTTCAGTGACTTTTCTA TGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACT CATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGGGT TCATTCATCATCTCCAGAGACAACTCCAAGAACACGCTCTATCTCCAACT GAACAGCCTGGGAGCTGAGGACACGGCTCTGTATTACTGTGCGAGAGAT GCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACTACTGGGGCCC GGGAACCCTGGTCACCGTCTCCTCA 193 3074 1106 QVQLVQSGGGVVQPGRSLRLSCAASGFTFSDFSMHWVRQAPGKGLEWVAL ISNDGSNKYYSDSLKGSFIISRDNSKNTLYLQLNSLGAEDTALYYCARDAVP HYDYVWGNFDYWGPGTLVTVSS 193 3075 1107 FTFSDFSMH 193 3076 1108 TTCACCTTCAGTGACTTTTCTATGCAC 193 3077 1109 LISNDGSNKYYSDSLKG 193 3078 1110 CTCATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGG GT 193 3079 1111 ARDAVPHYDYVWGNFDY 193 3080 1112 GCGAGAGATGCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACT AC 193 3081 1113 CAGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGCGTCTCCTGGACAGTC GATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAATT ATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATAGT TTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA CGACGAGGCTGATTATTACTGCAGCTCATATACAAGTTTCACTCCCGTGG TATTCGGCGGAGGGACCAAGGTGACCGTCCTA 193 3082 1114 QPVLTQPASVSASPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLIVYE VSNRPSGVSNRFSGSKSGNTASLTISGLQADDEADYYCSSYTSFTPVVFGGG TKVTVL 193 3083 1115 TGTSSDVGGYNYVS 193 3084 1116 ACTGGAACCAGCAGTGACGTTGGTGGTTATAATTATGTCTCC 193 3085 1117 EVSNRPS 193 3086 1118 GAGGTCAGTAATCGGCCCTCA 193 3087 1119 SSYTSFTPVV 193 3088 1120 AGCTCATATACAAGTTTCACTCCCGTGGTA 194 3089 1121 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACTTTTAGCGACTTTGCC ATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAC TTATTAAAAGTAGTGATTATGCATACTATGCAGACTCCGTGAGGGGCCG GTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCGAATG AACAGCCTGAGAGCCGACGACACGGCCGTATATTACTGTGCGAAAGACG CCGATTTTTGGAGTGGTGATTCCTACAATGGAGGGTACAACTTTGACTCC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 194 3090 1122 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFAMSWVRQAPGKGLEWVSLI KSSDYAYYADSVRGRFTISRDNSKNTLYLRMNSLRADDTAVYYCAKDADF WSGDSYNGGYNFDSWGQGTLVTVSS 194 3091 1123 FTFSDFAMS 194 3092 1124 TTCACTTTTAGCGACTTTGCCATGAGC 194 3093 1125 LIKSSDYAYYADSVRG 194 3094 1126 CTTATTAAAAGTAGTGATTATGCATACTATGCAGACTCCGTGAGGGGC 194 3095 1127 AKDADFWSGDSYNGGYNFDS 194 3096 1128 GCGAAAGACGCCGATTTTTGGAGTGGTGATTCCTACAATGGAGGGTACA ACTTTGACTCC 194 3097 1129 GATATTGTGCTGACCCAGTCTCCAGCCACCCTGTCTGTATCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCACCAACTTG GCCTGGTACCAGCAAAAACCTGGCCAGGCTCCCCGGCTCCTCATCTTTGG TGCCTCAACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGG TCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTT TGCAGTTTATTACTGTCAGCAGTATAATAAGTGGCCTCCGCTCACTTTCG GCGGAGGGACCAAAGTGGATATCAAA 194 3098 1130 DIVLTQSPATLSVSPGERATLSCRASQSVGTNLAWYQQKPGQAPRLLIFGAS TRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNKWPPLTFGGGTK VDIK 194 3099 1131 RASQSVGTNLA 194 3100 1132 AGGGCCAGTCAGAGTGTTGGCACCAACTTGGCC 194 3101 1133 GASTRAT 194 3102 1134 GGTGCCTCAACCAGGGCCACT 194 3103 1135 QQYNKWPPLT 194 3104 1136 CAGCAGTATAATAAGTGGCCTCCGCTCACT 195 3105 1137 CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCATCTTCAGTGACTACTAC ATGGTCTGGATCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAT ACATTAGTAGTAGCAGCAGATACATAAACTACGCAGACTCTGTGAAGGG CCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTTTCTGCAA ATGAACACCGTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCAAG GCTGGTATTCCGATTTTTGGAGTGGTCCCATTAGGATTTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 195 3106 1138 QVQLVQSGGGLVKPGGSLRLSCAASGFIFSDYYMVWIRQAPGKGLEWVSYI SSSSRYINYADSVKGRFTISRDNAKNSLFLQMNTVRAEDTAVYYCAQGWYS DFWSGPIRIWGQGTLVTVSS 195 3107 1139 FIFSDYYMV 195 3108 1140 TTCATCTTCAGTGACTACTACATGGTC 195 3109 1141 YISSSSRYINYADSVKG 195 3110 1142 TACATTAGTAGTAGCAGCAGATACATAAACTACGCAGACTCTGTGAAGG GC 195 3111 1143 AQGWYSDFWSGPIRI 195 3112 1144 GCGCAAGGCTGGTATTCCGATTTTTGGAGTGGTCCCATTAGGATT 195 3113 1145 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGTAACTCTTTA AATTGGTTTCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGATCTTCG ATGCATACAATCTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGG ATCTGGGACAGATTTTACCCTCACCATCAGCAGCCTGCAGCCTGAAGAT ATTGCAACATATTACTGTCAGCAGAATGATAATCTCGTTCTCACTITCGG CGGAGGGACCAAGCTGGAGATCAAA 195 3114 1146 DIQLTQSPSSLSASVGDRVTITCQASQDISNSLNWFQQKPGKAPKLLIFDAYN LETGVPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQNDNLVLTFGGGTKLEI K 195 3115 1147 QASQDISNSLN 195 3116 1148 CAGGCGAGTCAGGACATTAGTAACTCTTTAAAT 195 3117 1149 DAYNLET 195 3118 1150 GATGCATACAATCTGGAAACA 195 3119 1151 QQNDNLVLT 195 3120 1152 CAGCAGAATGATAATCTCGTTCTCACT 196 3121 1153 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACGTTTGATAATTACCCC ATGCACTGGATCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAG GTATTAGTTGGCATAGTGGAAGCATAGGCTATGCGGACTCTGTGAAGGG CCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAA ATGAACAGTCTGAGAACTGAGGACACGGCCTTGTATTACTGTGCAAAAG ACGCCCATTACTTTGATAATAGCGGTCACTACTACTACGGTCTGGACGTC TGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 196 3122 1154 QVQLVESGGGLVQPGRSLRLSCAASGFTFDNYPMHWIRQAPGKGLEWVSGI SWHSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKDAH YFDNSGHYYYGLDVWGQGTTVTVSS 196 3123 1155 FTFDNYPMH 196 3124 1156 TTCACGTTTGATAATTACCCCATGCAC 196 3125 1157 GISWHSGSIGYADSVKG 196 3126 1158 GGTATTAGTTGGCATAGTGGAAGCATAGGCTATGCGGACTCTGTGAAGG GC 196 3127 1159 AKDAHYFDNSGHYYYGLDV 196 3128 1160 GCAAAAGACGCCCATTACTTTGATAATAGCGGTCACTACTACTACGGTCT GGACGTC 196 3129 1161 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAATATTATCAACAACTTA GCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTCTG GTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGAGTTCACTCTCACCATCACCAGCCTGCAGTCTGAAGATT TTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCGCTCACTTTCGGC GGAGGGACCAAAGTGGATATCAAA 196 3130 1162 EIVLTQSPATLSVSPGERATLSCRASQNIINNLAWYQQKPGQAPRLLISGAST RATGIPARFSGSGSGTEFTLTITSLQSEDFAVYYCQQYNNWPLTFGGGTKVD IK 196 3131 1163 RASQNIINNLA 196 3132 1164 AGGGCCAGTCAGAATATTATCAACAACTTAGCC 196 3133 1165 GASTRAT 196 3134 1166 GGTGCATCCACCAGGGCCACT 196 3135 1167 QQYNNWPLT 196 3136 1168 CAGCAGTATAATAACTGGCCGCTCACT 197 3137 1169 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGT CCCTGAGACTCTCCTGTACAGCCTCTGGATTCAGCTTCAGTGATTATGGA GTGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATAGGTT TCGTCAGAACCAAGGGTTATGGAGGGACAACAGAGTACGCCGCGTCTGT GAGAGGCAGATTCACCATCTCAAGAGATGACTCCAAAAGCGTCGCCTAT CTACAATTGAACAGCCTGAAAGTCGAGGATACAGCCGTCTATTACTGTT CTGGGGCATCACGGGGCTTTTGGAGTGGGCCAACCTACTACTACTTTGGT ATGGACGTCTGGGGCCATGGGACCACGGTCACTGTCTCCTCA 197 3138 1170 QVQLVQSGGGLVQPGRSLRLSCTASGFSFSDYGVTWVRQAPGKGLEWIGFV RTKGYGGTTEYAASVRGRFTISRDDSKSVAYLQLNSLKVEDTAVYYCSGAS RGFWSGPTYYYFGMDVWGHGTTVTVSS 197 3139 1171 FSFSDYGVT 197 3140 1172 TTCAGCTTCAGTGATTATGGAGTGACC 197 3141 1173 FVRTKGYGGTTEYAASVRG 197 3142 1174 TTCGTCAGAACCAAGGGTTATGGAGGGACAACAGAGTACGCCGCGTCTG TGAGAGGC 197 3143 1175 SGASRGFWSGPTYYYFGMDV 197 3144 1176 TCTGGGGCATCACGGGGCTTTTGGAGTGGGCCAACCTACTACTACTTTGG TATGGACGTC 197 3145 1177 GAAATTGTGTTGACACAGTCTCCACTCTCCCTGGCCGTCACCCCTGGAGA GCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATGGTAATG GATACAACTACTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACA ACTCCTGATCTTTTGGGGTTCTTATCGGGCCTCCGGGGCCCCTGACAGGT TCAGTGCCAGTGGATCAGGCTCAGAGTTTACACTGAAAATCAGAAGAGT GGAGGCTGAGGATGTGGGGGTTTATTACTGCATGCAACCTCTACAAACA ACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 197 3146 1178 EIVLTQSPLSLAVTPGEPASISCRSSQSLLHGNGYNYLDWYLQKPGQSPQLLI FWGSYRASGAPDRFSASGSGSEFTLKIRRVEAEDVGVYYCMQPLQTTFGQG TKVDIK 197 3147 1179 RSSQSLLHGNGYNYLD 197 3148 1180 AGGTCTAGTCAGAGCCTCCTGCATGGTAATGGATACAACTACTTGGAT 197 3149 1181 WGSYRAS 197 3150 1182 TGGGGTTCTTATCGGGCCTCC 197 3151 1183 MQPLQTT 197 3152 1184 ATGCAACCTCTACAAACAACT 198 3153 1185 CAGGTCCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAG TCTCTAAAGATCTCCTGTAAGGGTTCTGGATACACCTTTAGAATGTATTG GATCGGCTGGGCGCGCCTGCTGCCCGGGAAAGGCCTGGAGTGGATAGGA ATCATCTATCCTGGTGACTCTGATACCAGGTACAACCCGTCCCTCCAAGG CCAGGTCACCATGTCAGTCGACAAGTCCATCAACACCGCCTACCTCCAG TGGGGAAGCCTGAAGGCCTCGGACAGCGCCATTTATTACTGTGCGAGAC TGAGATTACATCCCCAGAGTGGAATGGACGTCTGGGGCCAAGGGACCCT GGTCACCGTCTCCTCA 198 3154 1186 QVQLVQSGAEVKKPGESLKISCKGSGYTFRMYWIGWARLLPGKGLEWIGII YPGDSDTRYNPSLQGQVTMSVDKSINTAYLQWGSLKASDSAIYYCARLRLH PQSGMDVWGQGTLVTVSS 198 3155 1187 YTFRMYWIG 198 3156 1188 TACACCTTTAGAATGTATTGGATCGGC 198 3157 1189 IIYPGDSDTRYNPSLQG 198 3158 1190 ATCATCTATCCTGGTGACTCTGATACCAGGTACAACCCGTCCCTCCAAGG C 198 3159 1191 ARLRLHPQSGMDV 198 3160 1192 GCGAGACTGAGATTACATCCCCAGAGTGGAATGGACGTC 198 3161 1193 AATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGAC GGTAGTTATCTCCTGCACCCGCAGCAGTGGCAGCATTGCCGGCTACTATG TGCAGTGGTACCAACATCGCCCGGGCAGTTCCCCCACTACTGTGATATAT GAGGATGACCAAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGGGTCCG TCGACAGCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGAAGACT GAGGACGAGGCTGACTACTATTGTCAGTCCTATGATAACGCCATTTGGG TGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 198 3162 1194 NFMLTQPHSVSESPGKTVVISCTRSSGSIAGYYVQWYQHRPGSSPTTVIYED DQRPSGVPDRFSGSVDSSSNSASLTISGLKTEDEADYYCQSYDNAIWVFGGG TKLTVL 198 3163 1195 TRSSGSIAGYYVQ 198 3164 1196 ACCCGCAGCAGTGGCAGCATTGCCGGCTACTATGTGCAG 198 3165 1197 EDDQRPS 198 3166 1198 GAGGATGACCAAAGACCCTCT 198 3167 1199 QSYDNAIWV 198 3168 1200 CAGTCCTATGATAACGCCATTTGGGTG 199 3169 1201 CAGGTGCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGC TATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA GGGATCATCCCTATCTTTGGTACAGTAAACTACGCACAGAAGTTCCAGG GCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGA GCTGAGCAGTCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGA GATCGTTCGGTGACCCCTCGCTACTACGGTATGGACGTCTGGGGCCAAG GGACCACGGTCACCGTCTCCTCA 199 3170 1202 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGG IIPIFGTVNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDRSVT PRYYGMDVWGQGTTVTVSS 199 3171 1203 GTFSSYAIS 199 3172 1204 GGCACCTTCAGCAGCTATGCTATCAGC 199 3173 1205 GIIPIFGTVNYAQKFQG 199 3174 1206 GGGATCATCCCTATCTTTGGTACAGTAAACTACGCACAGAAGTTCCAGG GC 199 3175 1207 ARDRSVTPRYYGMDV 199 3176 1208 GCGAGAGATCGTTCGGTGACCCCTCGCTACTACGGTATGGACGTC 199 3177 1209 GAAATTGTGATGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTA GCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCACCGTAGCAACTGGCCTCCACTCACTTT CGGCCCTGGGACCAAGCTGGAGATCAAA 199 3178 1210 EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHRSNWPPLTFGPGTKL EIK 199 3179 1211 RASQSVSSYLA 199 3180 1212 AGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCC 199 3181 1213 DASNRAT 199 3182 1214 GATGCATCCAACAGGGCCACT 199 3183 1215 QHRSNWPPLT 199 3184 1216 CAGCACCGTAGCAACTGGCCTCCACTCACT 200 3185 1217 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCGGGATTCACCATCAGTGGTTATAAC ATGTTCTGGGTCCGCCAGCCTCCGGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGGC CGTTTCATCGTCTCCAGAGACAACGCCAAGAATTCACTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTTCTGTGCGAGAGCA CCTCTTTTACCCGCTATGATGGACCTCTGGGGCCAAGGGACCACGGTCAC CGTCTCCTCA 200 3186 1218 EVQLLESGGGLVKPGGSLRLSCAASGFTISGYNMFWVRQPPGKGLEWVSSI TAGSSYLNYADSVKGRFIVSRDNAKNSLYLQMNSLRAEDTAVYFCARAPLL PAMMDLWGQGTTVTVSS 200 3187 1219 FTISGYNMF 200 3188 1220 TTCACCATCAGTGGTTATAACATGTTC 200 3189 1221 SITAGSSYLNYADSVKG 200 3190 1222 TCCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGG C 200 3191 1223 ARAPLLPAMMDL 200 3192 1224 GCGAGAGCACCTCTTTTACCCGCTATGATGGACCTC 200 3193 1225 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATCTATACTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCCTGAATGG TTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA 200 3194 1226 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYT NNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLNGYVFG TGTKVTVL 200 3195 1227 TGSSSNIGAGYDVH 200 3196 1228 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 200 3197 1229 TNNNRPS 200 3198 1230 ACTAACAACAATCGGCCCTCA 200 3199 1231 QSYDRSLNGYV 200 3200 1232 CAGTCCTATGACAGAAGCCTGAATGGTTATGTC 201 3201 1233 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGCAGACACCTTCAGCAGTTATGCT ATCAGCTGGGTGCGGCAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GGATCCTCCCTATCCTTGGTACAGCAAACTCCGCACAGAAGTTCCGGGG CAGAGTCACGTTTACCGCGGACGAATCCACGACCACAGCCTACATGGAA CTGAGCAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGCGCGAGGC TTGCTGGACCACGGTGGCCGGGGTACGGTATGGACGTCTGGGGCCAAGG GACCCTGGTCACCGTCTCCTCA 201 3202 1234 EVQLVESGAEVKKPGSSVKVSCKASADTFSSYAISWVRQAPGQGLEWMGGI LPILGTANSAQKFRGRVTFTADESTTTAYMELSSLRSEDTAVYYCARLAGPR WPGYGMDVWGQGTLVTVSS 201 3203 1235 DTFSSYAIS 201 3204 1236 GACACCTTCAGCAGTTATGCTATCAGC 201 3205 1237 GILPILGTANSAQKFRG 201 3206 1238 GGGATCCTCCCTATCCTTGGTACAGCAAACTCCGCACAGAAGTTCCGGG GC 201 3207 1239 ARLAGPRWPGYGMDV 201 3208 1240 GCGAGGCTTGCTGGACCACGGTGGCCGGGGTACGGTATGGACGTC 201 3209 1241 GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCTTCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTA GCCTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATG CTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGG ATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGAT TTTGCAACTTATTACTGTCAGCAGCTTAACAGTTTCCCCCTCACCTTCGG CGGAGGGACCAAGGTGGAAATCAAA 201 3210 1242 DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAAST LQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSFPLTFGGGTKVEIK 201 3211 1243 RASQGISSYLA 201 3212 1244 CGGGCCAGTCAGGGCATTAGCAGTTATTTAGCC 201 3213 1245 AASTLQS 201 3214 1246 GCTGCATCCACTTTGCAAAGT 201 3215 1247 QQLNSFPLT 201 3216 1248 CAGCAGCTTAACAGTTTCCCCCTCACC 202 3217 1249 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGACGAAGCCTGGGGCCT CAGTGAGGGTCTCCTGCAAATTTTCCGCATACACCCTCTCTGCATTATCC ATTCACTGGGTGCGACAGGCTCCTGGAAAAGGCCTTGAGTGGATGGGAG CTTTTGATCCTGAGGATGGTGAGCCAATCTACTCACAGCATTTCCAGGGC AGAGTCACCATGACCGAGGACACTTCTACACAGACAGCCTACATGGAGC TGAACAGCCTGAGATCTGAGGACACGGCCGTTTATTACTGTTCATCCGTA GGACCAGCGGGGTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCG TCTCCTCA 202 3218 1250 QVQLVQSGAEVTKPGASVRVSCKFSAYTLSALSIHWVRQAPGKGLEWMGA FDPEDGEPIYSQHFQGRVTMTEDTSTQTAYMELNSLRSEDTAVYYCSSVGP AGWFDPWGQGTLVTVSS 202 3219 1251 YTLSALSIH 202 3220 1252 TACACCCTCTCTGCATTATCCATTCAC 202 3221 1253 AFDPEDGEPIYSQHFQG 202 3222 1254 GCTTTTGATCCTGAGGATGGTGAGCCAATCTACTCACAGCATTTCCAGGG C 202 3223 1255 SSVGPAGWFDP 202 3224 1256 TCATCCGTAGGACCAGCGGGGTGGTTCGACCCC 202 3225 1257 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGA CAGAGTCAGCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTA CATTGGTATCAACAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATG CTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGTCAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATT TTGCAACTTACTACTGTCACCAGAGTTACATTCCCCCATTCACTTTCGGC CCTGGGACCAAGCTGGAGATCAAA 202 3226 1258 DIRLTQSPSSLSASVGDRVSITCRASQSISSYLHWYQQKPGKAPKLLIYAASS LQSGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCHQSYIPPFTFGPGTKLEIK 202 3227 1259 RASQSISSYLH 202 3228 1260 CGGGCAAGTCAGAGCATTAGCAGCTATTTACAT 202 3229 1261 AASSLQS 202 3230 1262 GCTGCATCCAGTTTGCAAAGT 202 3231 1263 HQSYIPPFT 202 3232 1264 CACCAGAGTTACATTCCCCCATTCACT 203 3233 1265 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCACTAGCTATGGC ATGAACTGGGTCCGCCAGGCTCCAGGAAAGGGGCTGGAGTGGGTCTCAT CCATTAGTAGTAGTAGTAGTTTCATACACTATGGAGACTCAGTGAAGGG TCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAA ATGAACAGCCTGAGAGCCGGGGACACGGCTGTATACTACTGTGTGAGAG ACTCGGGCCACCAGGACTACCGCGGGGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 203 3234 1266 EVQLVESGGGLVKPGGSLRLSCAASGFTITSYGMNWVRQAPGKGLEWVSSI SSSSSFIHYGDSVKGRFTISRDNAKNSLYLQMNSLRAGDTAVYYCVRDSGH QDYRGDYWGQGTLVTVSS 203 3235 1267 FTITSYGMN 203 3236 1268 TTCACCATCACTAGCTATGGCATGAAC 203 3237 1269 SISSSSSFIHYGDSVKG 203 3238 1270 TCCATTAGTAGTAGTAGTAGTTTCATACACTATGGAGACTCAGTGAAGG GT 203 3239 1271 VRDSGHQDYRGDY 203 3240 1272 GTGAGAGACTCGGGCCACCAGGACTACCGCGGGGACTAC 203 3241 1273 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCTCCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATACTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAATGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGGAGCCTGAGTGG TTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 203 3242 1274 QSVVTQPPSVSGAPGQRVSISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYT NNNRPSGVPDRFSGSKSGTSASLAINGLQAEDEADYYCQSYDRSLSGWVFG GGTKLTVL 203 3243 1275 TGSSSNIGAGYDVH 203 3244 1276 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 203 3245 1277 TNNNRPS 203 3246 1278 ACTAACAACAATCGGCCCTCA 203 3247 1279 QSYDRSLSGWV 203 3248 1280 CAGTCCTATGACAGGAGCCTGAGTGGTTGGGTG 204 3249 1281 CAGGTGCAGCTGGTGGAGTCTGGTCCTGCGTTGGTGAAACCCACACAGA CCCTCACACTGACCTGCGCCTTCTCTGGGTTCTCACTCACCACTCGTGGG ATGTCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGC TTGCACGCATTGATTGGGATGATGATAAATACTACAGCACCTCTCTGAA GACCAGGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTC ACAATGAGCAACATGGACCCTGTGGACACAGCCACGTATTACTGTGCAC GGGCGTCTCTCTATGATAGTGGTGGCTATTACCTTTTTTTCTTTGACTACT GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 204 3250 1282 QVQLVESGPALVKPTQTLTLTCAFSGFSLTTRGMSVSWIRQPPGKALEWLA RIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMSNMDPVDTATYYCARAS LYDSGGYYLFFFDYWGQGTLVTVSS 204 3251 1283 FSLTTRGMSVS 204 3252 1284 TTCTCACTCACCACTCGTGGGATGTCTGTGAGC 204 3253 1285 RIDWDDDKYYSTSLKT 204 3254 1286 CGCATTGATTGGGATGATGATAAATACTACAGCACCTCTCTGAAGACC 204 3255 1287 ARASLYDSGGYYLFFFDY 204 3256 1288 GCACGGGCGTCTCTCTATGATAGTGGTGGCTATTACCTTTTTTTCTTTGAC TAC 204 3257 1289 GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGAGA CAGAGTCACCATCACTTGCCGGGCAAGCCAGAGCATTGGCAGTTATTTA AATTGGTATCAGCAGAAACCAGGGAAAGTCCCGAAACTCCTGATCTATG CTGCATCCAATTTGCAAGGTGGGGTCCCATCAAGGTTTCGTGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCAGCAATCTGCAACCTGAAGATT TTGCAAGTTACTACTGTCAACTGAGTTACAGTAGCCTTTGGACGTTCGGC CAAGGGACCAAGGTGGAAATCAAA 204 3258 1290 DIVMTQSPSSLSASVGDRVTITCRASQSIGSYLNWYQQKPGKVPKLLIYAAS NLQGGVPSRFRGSGSGTDFTLTISNLQPEDFASYYCQLSYSSLWTFGQGTKV EIK 204 3259 1291 RASQSIGSYLN 204 3260 1292 CGGGCAAGCCAGAGCATTGGCAGTTATTTAAAT 204 3261 1293 AASNLQG 204 3262 1294 GCTGCATCCAATTTGCAAGGT 204 3263 1295 QLSYSSLWT 204 3264 1296 CAACTGAGTTACAGTAGCCTTTGGACG 205 3265 1297 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGAGTCTCCTGTGCAGCCTCTGGATTTGACTTCAGTAACTATGCC ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAC TTATATCCTATGATGGAAATAATAAAGTCTATGCAGACTCCGTGAAGGG CCGATTCACCGTCTCCAGAGACAATTCCAAAAACACACTTTATCTGCAA ATGAACAGCCTGAGACCTGAAGACACGGCTGTGATTTACTGTGCGAAAG ATGGCTATCTGGCTCCTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTC TCCTCA 205 3266 1298 QVQLVESGGGVVQPGRSLRVSCAASGFDFSNYAMHWVRQAPGKGLEWVA LISYDGNNKVYADSVKGRFTVSRDNSKNTLYLQMNSLRPEDTAVIYCAKDG YLAPDFWGQGTLVTVSS 205 3267 1299 FDFSNYAMH 205 3268 1300 TTTGACTTCAGTAACTATGCCATGCAC 205 3269 1301 LISYDGNNKVYADSVKG 205 3270 1302 CTTATATCCTATGATGGAAATAATAAAGTCTATGCAGACTCCGTGAAGG GC 205 3271 1303 AKDGYLAPDF 205 3272 1304 GCGAAAGATGGCTATCTGGCTCCTGACTTC 205 3273 1305 CAGTCAGTCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTC GATCATCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGAATATGAC TATGTCTCCTGGTACCAACACCACCCACACAAAGCCCCCAAACTCATAA TTTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGC TCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA GGACGAGGCTGATTATTACTGCAGTTCCTACACAAGCAGTAGCGGTCAA GCCTTCGGAACTGGGACCAAGGTCACCGTCCTA 205 3274 1306 QSVLTQPASVSGSPGQSIIISCTGTSSDVGEYDYVSWYQHHPHKAPKLIIYEV SNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSGQAFGTGT KVTVL 205 3275 1307 TGTSSDVGEYDYVS 205 3276 1308 ACTGGAACCAGCAGTGACGTTGGTGAATATGACTATGTCTCC 205 3277 1309 EVSNRPS 205 3278 1310 GAGGTCAGTAATCGGCCCTCA 205 3279 1311 SSYTSSSGQA 205 3280 1312 AGTTCCTACACAAGCAGTAGCGGTCAAGCC 206 3281 1313 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGATCCAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCGTCAGTAGCAAGTAC ATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAA TTATTTATAGTGGTGGTAGCACATACCACGCAGACTCCGTGAAGGGCCG ATTCACCATCTCCAGAGACAACTCCAAGAACACACTGTATCTTCAAATG AACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGATG ATTACGATTTTTGGAGTGGCAACGGCCCACCGGAGATGGCCGTCTGGGG CCAGGGGACCACGGTCACCGTCTCCTCA 206 3282 1314 EVQLVESGGGLIQPGGSLRLSCAASGFTVSSKYMSWVRQAPGKGLEWVSII YSGGSTYHADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDYD FWSGNGPPEMAVWGQGTTVTVSS 206 3283 1315 FTVSSKYMS 206 3284 1316 TTCACCGTCAGTAGCAAGTACATGAGC 206 3285 1317 IIYSGGSTYHADSVKG 206 3286 1318 ATTATTTATAGTGGTGGTAGCACATACCACGCAGACTCCGTGAAGGGC 206 3287 1319 ARDDYDFWSGNGPPEMAV 206 3288 1320 GCGAGAGATGATTACGATTTTTGGAGTGGCAACGGCCCACCGGAGATGG CCGTC 206 3289 1321 GACATCCGGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCGAGTCAGGGCATTAGCAATTATTTA GCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATG CTGCATCCACTTTGCAATCAGGGGTCCCATCTCGGTTCAGTGGCAGTGGA TCTGAGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGT TGCAACTTATTACTGTCAAAAGTATAACAGTGTCCCTCTGACGTTCGGCC AAGGGACCAAGGTGGAAATCAAA 206 3290 1322 DIRMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAAS TLQSGVPSRFSGSGSETDFTLTISSLQPEDVATYYCQKYNSVPLTFGQGTKVE IK 206 3291 1323 RASQGISNYLA 206 3292 1324 CGGGCGAGTCAGGGCATTAGCAATTATTTAGCC 206 3293 1325 AASTLQS 206 3294 1326 GCTGCATCCACTTTGCAATCA 206 3295 1327 QKYNSVPLT 206 3296 1328 CAAAAGTATAACAGTGTCCCTCTGACG 207 3297 1329 CAGGTCCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAG TCTCTGAAGATCTCCTGTAAGACTTCTGGATACAGATTTACCAATTACTG GATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGG GATCATCTATCCTGGTGACTCTGATGCCAGATACAGCCCGTCCTTCCAAG GCCAGGTCACCTTCTCAGCCGACAAGTCCATCAGCACCGCCTACCTGCA CTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGA CAAGATGACAGTGGCTGGGCCGACTTCTTTCCCTTTGACTACTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCA 207 3298 1330 QVQLVQSGAEVKKPGESLKISCKTSGYRFTNYWIGWVRQMPGKGLEWMGI IYPGDSDARYSPSFQGQVTFSADKSISTAYLHWSSLKASDTAMYYCARQDD SGWADFFPFDYWGQGTLVTVSS 207 3299 1331 YRFTNYWIG 207 3300 1332 TACAGATTTACCAATTACTGGATCGGC 207 3301 1333 ITYPGDSDARYSPSFQG 207 3302 1334 ATCATCTATCCTGGTGACTCTGATGCCAGATACAGCCCGTCCTTCCAAGG C 207 3303 1335 ARQDDSGWADFFPFDY 207 3304 1336 GCGAGACAAGATGACAGTGGCTGGGCCGACTTCTTTCCCTTTGACTAC 207 3305 1337 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCACAGTTTTAGCAGCACCTAC TTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGCTGCATCCAACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAG TGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAA GATTTTGCAGTGTATTTCTGTCAGCAGTATGATAGCTCACCGTGGACGTT CGGCCAAGGGACCAAGCTGGAGATCAAA 207 3306 1338 EIVLTQSPGTLSLSPGERATLSCRASHSFSSTYLAWYQQKPGQAPRLLIYAAS NRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYFCQQYDSSPWTFGQGTKLE IK 207 3307 1339 RASHSFSSTYLA 207 3308 1340 AGGGCCAGTCACAGTTTTAGCAGCACCTACTTAGCC 207 3309 1341 AASNRAT 207 3310 1342 GCTGCATCCAACAGGGCCACT 207 3311 1343 QQYDSSPWT 207 3312 1344 CAGCAGTATGATAGCTCACCGTGGACG 208 3313 1345 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAGGACTTCTGGAGGCACCTTCAGCAGCTTTTCT ATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAATGGATGGGAG GGATCATCCCTATCTTTGGGACAGCAAACTACGCAAAGAAATTCCAGGG CAGAGTCACAATTACCGCGGACGAATCCACGGACACAGCCTATATGGAA CTGAGGAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTGCGAGAG ATTCCCCCAAAATATCAGCAACTGAATATTACTTTGACTACTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCA 208 3314 1346 QVQLVQSGAEVKKPGSSVKVSCRTSGGTFSSFSISWVRQAPGQGLEWMGGI IPIFGTANYAKKFQGRVTITADESTDTAYMELRSLRSEDTAVYYCARDSPKIS ATEYYFDYWGQGTLVTVSS 208 3315 1347 GTFSSFSIS 208 3316 1348 GGCACCTTCAGCAGCTTTTCTATCAGC 208 3317 1349 GIIPIFGTANYAKKFQG 208 3318 1350 GGGATCATCCCTATCTTTGGGACAGCAAACTACGCAAAGAAATTCCAGG GC 208 3319 1351 ARDSPKISATEYYFDY 208 3320 1352 GCGAGAGATTCCCCCAAAATATCAGCAACTGAATATTACTTTGACTAC 208 3321 1353 GACATCCAGGTGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTTTTACTAGTTGGTTGG CCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAA GGCGTCTACTTTAGACAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGA TCTGGGACAGAATTCACTCTCACCATCAACGGCCTGCAGCCTGATGATTT TGCAACTTACTACTGCCAACACTATGATAGTTATTCGGGGACCTTCGGCC AAGGGACACGACTGGAGATTAAA 208 3322 1354 DIQVTQSPSTLSASVGDRVTITCRASQSFTSWLAWYQQKPGKAPKLLIYKAS TLDSGVPSRFSGSGSGTEFTLTINGLQPDDFATYYCQHYDSYSGTFGQGTRL EIK 208 3323 1355 RASQSFTSWLA 208 3324 1356 CGGGCCAGTCAGAGTTTTACTAGTTGGTTGGCC 208 3325 1357 KASTLDS 208 3326 1358 AAGGCGTCTACTTTAGACAGT 208 3327 1359 QHYDSYSGT 208 3328 1360 CAACACTATGATAGTTATTCGGGGACC 209 3329 1361 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTACGCC ATGAGCTGGGTCCGCCAGATTCCAGGGAAGGGGCTGGAGTGGGTCTCAA CAATCAATATTAGTGGTGGTAGTACATACTACGCAGACTCCGTGAAGGG CCGGTTCACCATCTCCAGAGACAATTCCAGGGACACGGTGTTTCTACAA ATGAATGGCCTGAGAGCCGAGGACACGGCCCTATATTACTGCGCGAGGG GATATCATATAGACTGGTTTGACTTTTGGGGCCAGGGAACCCTGGTCACC GTCTCCTCA 209 3330 1362 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQIPGKGLEWVSTI NISGGSTYYADSVKGRFTISRDNSRDTVFLQMNGLRAEDTALYYCARGYHI DWFDFWGQGTLVTVSS 209 3331 1363 FTFSSYAMS 209 3332 1364 TTCACCTTTAGCAGCTACGCCATGAGC 209 3333 1365 TINISGGSTYYADSVKG 209 3334 1366 ACAATCAATATTAGTGGTGGTAGTACATACTACGCAGACTCCGTGAAGG GC 209 3335 1367 ARGYHIDWFDF 209 3336 1368 GCGAGGGGATATCATATAGACTGGTTTGACTTT 209 3337 1369 GATATTGTGCTGACTCAGACTCCATCTTCCGTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGTCGGGCGAGTCAGGATATTGGCAGCTGGTTA GCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTCAATTCCTGATCTATG CTGCATCCCAATTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGG ATCTGGGACAGATTTCACTCTTACCATCAGCAGCCTGCAGCCTGAAGATT TTGCAACTTACTATTGTCAACAGGCTAAAAGTTTACCTCGGACTTTCGGC GGAGGGACCAAAGTGGATATCAAA 209 3338 1370 DIVLTQTPSSVSASVGDRVTITCRASQDIGSWLAWYQQKPGKAPQFLIYAAS QLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKSLPRTFGGGTKV DIK 209 3339 1371 RASQDIGSWLA 209 3340 1372 CGGGCGAGTCAGGATATTGGCAGCTGGTTAGCC 209 3341 1373 AASQLQS 209 3342 1374 GCTGCATCCCAATTGCAAAGT 209 3343 1375 QQAKSLPRT 209 3344 1376 CAACAGGCTAAAAGTTTACCTCGGACT 210 3345 1377 GAGGTGCAGCTGTTGGAGTCTGGAGGAGGCTTGATCCAGCCTGGGGGGT CCCTGAGACTCTCCTGTGGAGCCTCTGGGTTCACCGTCACTGGCAACTAC ATGCATTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAG TTATTTATGCCGGTTCTAGCACATATTACGCAGACTCCGTGAGGGGCCGA TTCACCATCTCCAGAGACAAGGCCAGGAACACGTTGTTTCTTCAAATGA ATAGACTGAGAGCCGAGGACACGGCCGTGTATTATTGTGCGAGAGCGGG GGTAGTTGGGGAAGATAGAAGTGGCTGGTACGGTCCCGATTATTTCCAC GGTTTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 210 3346 1378 EVQLLESGGGLIQPGGSLRLSCGASGFTVTGNYMHWVRQAPGKGLEWVSVI YAGSSTYYADSVRGRFTISRDKARNTLFLQMNRLRAEDTAVYYCARAGVV GEDRSGWYGPDYFHGLDVWGQGTTVTVSS 210 3347 1379 FTVTGNYMH 210 3348 1380 TTCACCGTCACTGGCAACTACATGCAT 210 3349 1381 VIYAGSSTYYADSVRG 210 3350 1382 GTTATTTATGCCGGTTCTAGCACATATTACGCAGACTCCGTGAGGGGC 210 3351 1383 ARAGVVGEDRSGWYGPDYFHGLDV 210 3352 1384 GCGAGAGCGGGGGTAGTTGGGGAAGATAGAAGTGGCTGGTACGGTCCC GATTATTTCCACGGTTTGGACGTC 210 3353 1385 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTCGCAACAACTA CTTAGCCTGGTACCAGCAAAAACCTGGCCAGCCTCCCAGGCTCCTCATCT ATGGTGAATCCAGAAGGGCCACTGGCATCCCAGGCAGGTTCAGTGGCAG TGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAGCCTGAA GATTTTGCAGTGTATTACTGTCAGCAGTATGGTGGCTCACCGTACACTTT TGGCCAGGGGACCAAGGTGGATATCAAA 210 3354 1386 ETTLTQSPGTLSLSPGERATLSCRASQSIRNNYLAWYQQKPGQPPRLLIYGES RRATGIPGRFSGSGSGTDFTLTISSLEPEDFAVYYCQQYGGSPYTFGQGTKV DIK 210 3355 1387 RASQSIRNNYLA 210 3356 1388 AGGGCCAGTCAGAGTATTCGCAACAACTACTTAGCC 210 3357 1389 GESRRAT 210 3358 1390 GGTGAATCCAGAAGGGCCACT 210 3359 1391 QQYGGSPYT 210 3360 1392 CAGCAGTATGGTGGCTCACCGTACACT 211 3361 1393 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAGGGTCTCCTGCGAGGCTTCTGGAGGCACCTTCAGCACCTATGCT ATTAGCTGGGTGCGACAGGCCCCTGGACTAGGGCTTGAGTGGATGGGAG GGATCCACCCCATCTCTGGTACAGCAAACTACGCACAGAGCTTCCAGGA CAGACTCACCATTACCGTGGACAAGTCCACGAGCACAGCCTACATGGAC CTGAGCAGCCTGAGATCTGAGGACACGGCCATATATTATTGTGCGAGAG TTGGTCTGGGTCGCACTTGGATTTATGATACAATGGGTTACCTTGACTAC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 211 3362 1394 QVQLVQSGAEVKKPGSSVRVSCEASGGTFSTYAISWVRQAPGLGLEWMGGI HPISGTANYAQSFQDRLTITVDKSTSTAYMDLSSLRSEDTAIYYCARVGLGR TWIYDTMGYLDYWGQGTLVTVSS 211 3363 1395 GTFSTYAIS 211 3364 1396 GGCACCTTCAGCACCTATGCTATTAGC 211 3365 1397 GIHPISGTANYAQSFQD 211 3366 1398 GGGATCCACCCCATCTCTGGTACAGCAAACTACGCACAGAGCTTCCAGG AC 211 3367 1399 ARVGLGRTWIYDTMGYLDY 211 3368 1400 GCGAGAGTTGGTCTGGGTCGCACTTGGATTTATGATACAATGGGTTACCT TGACTAC 211 3369 1401 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA GAGAGTCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACGACTACTTA GCCTGGTACCAACAAAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCACCGTACCAACTGGCCTTCCCTCACTTTC GGCGGAGGGACCAAGGTGGAAATCAAA 211 3370 1402 EIVLTQSPATLSLSPGERVTLSCRASQSVNDYLAWYQQKPGQAPRLLIYDAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHRTNWPSLTFGGGTK VEIK 211 3371 1403 RASQSVNDYLA 211 3372 1404 AGGGCCAGTCAGAGTGTTAACGACTACTTAGCC 211 3373 1405 DASNRAT 211 3374 1406 GATGCATCCAACAGGGCCACT 211 3375 1407 QHRTNWPSLT 211 3376 1408 CAGCACCGTACCAACTGGCCTTCCCTCACT 212 3377 1409 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCGGGATTCACCATCAGTGGTTATAAC ATGTTCTGGGTCCGCCAGCCTCCGGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGGC CGTTTCATCGTCTCCAGAGACAACGCCAAGAATTCACTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTTCTGTGCGAGAGCA CCTCTTTTACCCGCTATGATGGACCTCTGGGGCCAAGGGACCACGGTCAC CGTCTCCTCA 212 3378 1410 EVQLVESGGGLVKPGGSLRLSCAASGFTISGYNMFWVRQPPGKGLEWVSSI TAGSSYLNYADSVKGRFIVSRDNAKNSLYLQMNSLRAEDTAVYFCARAPLL PAMMDLWGQGTTVTVSS 212 3379 1411 FTISGYNMF 212 3380 1412 TTCACCATCAGTGGTTATAACATGTTC 212 3381 1413 SITAGSSYLNYADSVKG 212 3382 1414 TCCATTACTGCTGGTAGTAGTTATTTAAACTATGCAGACTCAGTGAAGGG C 212 3383 1415 ARAPLLPAMMDL 212 3384 1416 GCGAGAGCACCTCTTTTACCCGCTATGATGGACCTC 212 3385 1417 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAACTCCTC ATCTATACTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCCTGAATGG TTATGTCTTCGGAACTGGGACCACGGTCACCGTCCTA 212 3386 1418 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYT NNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLNGYVFG TGTTVTVL 212 3387 1419 TGSSSNIGAGYDVH 212 3388 1420 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 212 3389 1421 TNNNRPS 212 3390 1422 ACTAACAACAATCGGCCCTCA 212 3391 1423 QSYDRSLNGYV 212 3392 1424 CAGTCCTATGACAGAAGCCTGAATGGTTATGTC 213 3393 1425 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCCCTGGATTCACCATCAGGAGTTATACC ATGTACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAT CCATTAGTAGTAGTAGTAGTTACATACACTATGGAGACTCAGTGAAGGG CCGATTCACCATCGCCAGAGACAATGCCAAGAACTCACTGTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGTGAGAG ATCATTGTACTGGTGGAAGCTGCTACTTAAACGGTATGGACGTCTGGGG CCAAGGGACCACGGTCACCGTCTCCTCA 213 3394 1426 EVQLVESGGGLVKPGGSLRLSCAAPGFTIRSYTMYWVRQAPGKGLEWVASI SSSSSYIHYGDSVKGRFTIARDNAKNSLYLQMNSLRAEDTAVYYCVRDHCT GGSCYLNGMDVWGQGTTVTVSS 213 3395 1427 FTIRSYTMY 213 3396 1428 TTCACCATCAGGAGTTATACCATGTAC 213 3397 1429 SISSSSSYIHYGDSVKG 213 3398 1430 TCCATTAGTAGTAGTAGTAGTTACATACACTATGGAGACTCAGTGAAGG GC 213 3399 1431 VRDHCTGGSCYLNGMDV 213 3400 1432 GTGAGAGATCATTGTACTGGTGGAAGCTGCTACTTAAACGGTATGGACG TC 213 3401 1433 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGACCAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGCGG TTCGGTATTCGGCGGAGGGACCAAGCTCACCGTCCTA 213 3402 1434 QPVLTQPPSVSGAPGQRVTISCTGTSSNIGAGYDVHWYQQLPGTAPKWYG NNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVFGG GTKLTVL 213 3403 1435 TGTSSNIGAGYDVH 213 3404 1436 ACTGGGACCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 213 3405 1437 GNNNRPS 213 3406 1438 GGTAACAACAATCGGCCCTCA 213 3407 1439 QSYDSSLSGSV 213 3408 1440 CAGTCCTATGACAGCAGCCTGAGCGGTTCGGTA 214 3409 1441 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGATCCAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCGTCAGTAGCAAGTAC ATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAA TTATTTATAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCG ATTCACCATCTCCAGAGACAATTCCAAGAACACACTGTATCTTCAAATG AACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGATG ATTACGATTTTTGGAGTGGCAACGGCCCACCGGAGATGGCCGTCTGGGG CCAGGGGACCACGGTCACCGTCTCCTCA 214 3410 1442 EVQLVESGGGLIQPGGSLRLSCAASGFTVSSKYMSWVRQAPGKGLEWVSII YSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDYD FWSGNGPPEMAVWGQGTTVTVSS 214 3411 1443 FTVSSKYMS 214 3412 1444 TTCACCGTCAGTAGCAAGTACATGAGC 214 3413 1445 IIYSGGSTYYADSVKG 214 3414 1446 ATTATTTATAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGC 214 3415 1447 ARDDYDFWSGNGPPEMAV 214 3416 1448 GCGAGAGATGATTACGATTTTTGGAGTGGCAACGGCCCACCGGAGATGG CCGTC 214 3417 1449 GACATGAGACTCACCCAGTCTCCATCCTCCCTGTCTGCGTCTGTAGGAGA CAGAGTCACCATCACTTGCCGGGCGAGTCAGGGCATTAGCAATTATTTA GCCTGGTATCAGCAGAGACCAGGGAAAGTTCCTCAGCTCCTGATCTATA CTGCATCCACTTTGCAATCAGGGGTCCCATCTCGGTTCAGTGGCAGTGGA TCTGAGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGT TGCAACTTATTACTGTCAAAAGTATGACAGTGTCCCTCTGACGTTCGGCC AAGGGACCAAGGTGGAAATCAAA 214 3418 1450 DMRLTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQRPGKVPQLLIYTAS TLQSGVPSRFSGSGSETDFTLTISSLQPEDVATYYCQKYDSVPLTFGQGTKVE IK 214 3419 1451 RASQGISNYLA 214 3420 1452 CGGGCGAGTCAGGGCATTAGCAATTATTTAGCC 214 3421 1453 TASTLQS 214 3422 1454 ACTGCATCCACTTTGCAATCA 214 3423 1455 QKYDSVPLT 214 3424 1456 CAAAAGTATGACAGTGTCCCTCTGACG 215 3425 1457 GAGGTGCAGCTGGTGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGA CCCTCACACTGACCTGCACCGTCTCGGGGGGTGTTGAGAGAATGAGTGT GAGTTGGGTCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTGCACGC ATTGATTGGGATGATGATAAATACTACAACACATTTCTGAAGACCAGGC TCACCATCTCCAAGGGCACCTCCAAAAACGAGGTGGTCCTTACAATGAC CAACATGGACCCTGAAGACACAGCAATTTATTACTGTGCACGGACGAAT CGCTATGATAAAAGTGGTTATTACCTTTATTACCTTGACTACTGGGGCCA GGGAACCCTGGTCACTGTCTCCTCA 215 3426 1458 EVQLVESGPALVKPTQTLTLTCTVSGGVERMSVSWVRQPPGKALEWLARID WDDDKYYNTFLKTRLTISKGTSKNEVVLTMTNMDPEDTAIYYCARTNRYD KSGYYLYYLDYWGQGTLVTVSS 215 3427 1459 GVERMSVS 215 3428 1460 GGTGTTGAGAGAATGAGTGTGAGT 215 3429 1461 RIDWDDDKYYNTFLKT 215 3430 1462 CGCATTGATTGGGATGATGATAAATACTACAACACATTTCTGAAGACC 215 3431 1463 ARTNRYDKSGYYLYYLDY 215 3432 1464 GCACGGACGAATCGCTATGATAAAAGTGGTTATTACCTTTATTACCTTGA CTAC 215 3433 1465 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGA CAAAGTCACCATCACTTGCCGGGCAAGTCAGACCATTGCCAGTTATGTA AATTGGTATCAGCAGCACCCAGGGAAAGCCCCTAAGCTCCTAATCTATC TTGCATCCCGTTTGCAAAGTGGTGCCCCATCAAGGTTCAGTGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCCTCAATCTGCAACCTGAAGATT TTGCAACTTACTACTGTCAACAGAGTTACAGTTCGTTTTTCACTTTCGGC CCTGGGACCAAGGTGGAAATCAAA 215 3434 1466 DIQMTQSPSSLSASVGDKVTITCRASQTIASYVNWYQQHPGKAPKLLIYLAS RLQSGAPSRFSGSGSGTDFTLTILNLQPEDFATYYCQQSYSSFFTFGPGTKVEI K 215 3435 1467 RASQTIASYVN 215 3436 1468 CGGGCAAGTCAGACCATTGCCAGTTATGTAAAT 215 3437 1469 LASRLQS 215 3438 1470 CTTGCATCCCGTTTGCAAAGT 215 3439 1471 QQSYSSFFT 215 3440 1472 CAACAGAGTTACAGTTCGTTTTTCACT 216 3441 1473 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTTTTCT ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAC TCATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGGG TTCATTCATCATCTCCAGAGACAACTCCAAGAACACGCTCTATCTCCAAC TGAACAGCCTGGGAGCTGAGGACACGGCTCTCTATTACTGTGCGAGAGA TGCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACTACTGGGGCC AGGGAACCCTGGTCACTGTCTCCTCA 216 3442 1474 EVQLLESGGGVVQPGRSLRLSCAASGFTFSDFSMHWVRQAPGKGLEWVALI SNDGSNKYYSDSLKGSFIISRDNSKNTLYLQLNSLGAEDTALYYCARDAVPH YDYVWGNFDYWGQGTLVTVSS 216 3443 1475 FTFSDFSMH 216 3444 1476 TTCACCTTCAGTGACTTTTCTATGCAC 216 3445 1477 LISNDGSNKYYSDSLKG 216 3446 1478 CTCATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGG GT 216 3447 1479 ARDAVPHYDYVWGNFDY 216 3448 1480 GCGAGAGATGCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACT AC 216 3449 1481 CAGTCTGTTCTGACTCAGCCTGCCTCCGTGTCTGCGTCTCCTGGACAGTC GATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAATT ATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATAAT TTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA CGACGAGGCTGATTATTACTGCAGCTCATATACAAGTTTCACTCCCGTGG TATTCGGCGGAGGGACCAAGCTGACCGTCCTA 216 3450 1482 QSVLTQPASVSASPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLIIYEV SNRPSGVSNRFSGSKSGNTASLTISGLQADDEADYYCSSYTSFTPVVFGGGT KLTVL 216 3451 1483 TGTSSDVGGYNYVS 216 3452 1484 ACTGGAACCAGCAGTGACGTTGGTGGTTATAATTATGTCTCC 216 3453 1485 EVSNRPS 216 3454 1486 GAGGTCAGTAATCGGCCCTCA 216 3455 1487 SSYTSFTPVV 216 3456 1488 AGCTCATATACAAGTTTCACTCCCGTGGTA 217 3457 1489 CAGGTCCAGCTTGTACAGTCTGGGGCGGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCTTGTAAGTCTTCTGGAGGGACCTTCAGCAACTATATT ATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GGATCGTCCCTCTCTCTGGAACAACAGACTACGCACAGAAGTTCCAGGG CCGAGTCACGATTACCGCGGACAAATCCACGACTACAGCCTACATGGAG CTTCGCACCTTGAGACCTGAGGACACGGCCGTCTATTATTGTGCGAGGG GGAGTGGTGGTAGCAATGCCTACTTCGACCCCTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 217 3458 1490 QVQLVQSGAEVKKPGSSVKVSCKSSGGTFSNYIISWVRQAPGQGLEWMGGI VPLSGTTDYAQKFQGRVTITADKSTTTAYMELRTLRPEDTAVYYCARGSGG SNAYFDPWGQGTLVTVSS 217 3459 1491 GTFSNYIIS 217 3460 1492 GGGACCTTCAGCAACTATATTATCAGC 217 3461 1493 GIVPLSGTTDYAQKFQG 217 3462 1494 GGGATCGTCCCTCTCTCTGGAACAACAGACTACGCACAGAAGTTCCAGG GC 217 3463 1495 ARGSGGSNAYFDP 217 3464 1496 GCGAGGGGGAGTGGTGGTAGCAATGCCTACTTCGACCCC 217 3465 1497 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCAGTGGCCCCAGGAAAGA CGGCCAAGATTACCTGTGGGGGAAACAACATTGGAAGTAAGAGTGTGTA CTGGTACCAACAGAAGCCAGGCCAGGCCCCTGTGCTGGTCATGTATTAT GATACTTACCGGCCCTCAGGGATCCCTGAGCGCTTCTCTGGCTCCAACTC TGGGAACTCGGCCACCCTGACCATCAGCAGAGTCGACGCCGGGGATGAG GCCGACTATTACTGTCAGGTGTGGGATAGTAGGAGTGATCATCCTTATGT CTTCGGAAGTGGGACCAAGCTCACCGTCCTA 217 3466 1498 QSVVTQPPSVSVAPGKTAKITCGGNNIGSKSVYWYQQKPGQAPVLVMYYD TYRPSGIPERFSGSNSGNSATLTISRVDAGDEADYYCQVWDSRSDHPYVFGS GTKLTVL 217 3467 1499 GGNNIGSKSVY 217 3468 1500 GGGGGAAACAACATTGGAAGTAAGAGTGTGTAC 217 3469 1501 YDTYRPS 217 3470 1502 TATGATACTTACCGGCCCTCA 217 3471 1503 QVWDSRSDHPYV 217 3472 1504 CAGGTGTGGGATAGTAGGAGTGATCATCCTTATGTC 218 3473 1505 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCGT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACGTCCAGCAGTTATAT TATCAGTTGGGTGCGACAGGCCCCTGGGCAAGGGCTTGAGTGGATGGGA GGGATCATCCCCATCCCTATTTCTGGCGCACCAACCTACGCACAGAAGTT CCAGGGCAGAGCAAACTATGCACAGAAGTTCGAGGGCAGACTCACGATT ACCGCGGACAGACTCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA CATCTGAGGACACGGCCGTGTATTATTGTGTAAGAGATGAGAGGAACGG GGGCTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 218 3474 1506 QVQLVQSGAEVKRPGSSVKVSCKASGGTSSSYIISWVRQAPGQGLEWMGGI IPIPISGAPTYAQKFQGRANYAQKFEGRLTITADRLTSTAYMELSSLTSEDTA VYYCVRDERNGGYWGQGTLVTVSS 218 3475 1507 GTSSSYIIS 218 3476 1508 GGCACGTCCAGCAGTTATATTATCAGT 218 3477 1509 GIIPIPISGAPTYAQKFQGRANYAQKFEG 218 3478 1510 GGGATCATCCCCATCCCTATTTCTGGCGCACCAACCTACGCACAGAAGTT CCAGGGCAGAGCAAACTATGCACAGAAGTTCGAGGGC 218 3479 1511 VRDERNGGY 218 3480 1512 GTAAGAGATGAGAGGAACGGGGGCTAT 218 3481 1513 CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTC GATCACCATCTCCTGCACTGGAACCAGCAATGACGTTGGTGCTTATAATC ATGTGTCGTGGTACCAACAACACCCAGGGAAAGCCCCCAAACTCATGAT CTATGATGTCACTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTTTGGGCTCCAGACTGAC GACGAGGCTGATTATTATTGCAGCTCATATACAATCAGCAGCACCTTGGT GTTCGGCGGAGGGACCCAGCTGACCGTCCTC 218 3482 1514 QSALTQPASVSGSPGQSITISCTGTSNDVGAYNHVSWYQQHPGKAPKLMIY DVTNRPSGVSNRFSGSKSGNTASLTIFGLQTDDEADYYCSSYTISSTLVFGGG TQLTVL 218 3483 1515 TGTSNDVGAYNHVS 218 3484 1516 ACTGGAACCAGCAATGACGTTGGTGCTTATAATCATGTGTCG 218 3485 1517 DVTNRPS 218 3486 1518 GATGTCACTAATCGGCCCTCA 218 3487 1519 SSYTISSTLV 218 3488 1520 AGCTCATATACAATCAGCAGCACCTTGGTG 219 3489 1521 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGGCTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTTCCTATGCA ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGCCTGGAGTGGGTGGCAG TTATATCATATGATGAAGGCAATGAATACTACGCAGACTCCGTGAAGGG CCGATTCACCATCTCCAGAGCCAATTCCAAGAACACGATTTATCTGCAA ATGAACAGCCTGAGAGCTGAGGACACGGCTGTCTATTACTGTGCGAGAG ATTACATACATGGGGACTACGGTTTGGACGTCTGGGGCCTAGGGACCAC GGTCACCGTCTCCTCA 219 3490 1522 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAV ISYDEGNEYYADSVKGRFTISRANSKNTIYLQMNSLRAEDTAVYYCARDYI HGDYGLDVWGLGTTVTVSS 219 3491 1523 FTFSSYAMH 219 3492 1524 TTCACCTTCAGTTCCTATGCAATGCAC 219 3493 1525 VISYDEGNEYYADSVKG 219 3494 1526 GTTATATCATATGATGAAGGCAATGAATACTACGCAGACTCCGTGAAGG GC 219 3495 1527 ARDYIHGDYGLDV 219 3496 1528 GCGAGAGATTACATACATGGGGACTACGGTTTGGACGTC 219 3497 1529 GAAATTGTGTTGACACAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGA GCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATG GATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACA GCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGT TCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGT GGAGGCTGAGGATGTTGGGGTTTACTACTGCATGCAACCTCTACAAACA ATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 219 3498 1530 EIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLI YLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQPLQTITFGQG TRLEIK 219 3499 1531 RSSQSLLHSNGYNYLD 219 3500 1532 AGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTATTTGGAT 219 3501 1533 LGSNRAS 219 3502 1534 TTGGGTTCTAATCGGGCCTCC 219 3503 1535 MQPLQTIT 219 3504 1536 ATGCAACCTCTACAAACAATCACC 220 3505 1537 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTACTAT ATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGGTGGGAT GGATCAACCCTAACAGTGGTTCCACAAACTATGCACAGAAGTTTCAGGG CAGGGTCACCGTGACCAGGGACACGTCCATCAGCACAGCCTACATGGAC CTGAGCAGACTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGCA GGAGCTGGGACCATGATGCTTTTGATATCTGGGGCCAAGGGACAATGGT CACTGTCTCCTCA 220 3506 1538 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWV GWINPNSGSTNYAQKFQGRVTVTRDTSISTAYMDLSRLRSDDTAVYYCASR SWDHDAFDIWGQGTMVTVSS 220 3507 1539 YTFTDYYMH 220 3508 1540 TACACCTTCACCGACTACTATATGCAC 220 3509 1541 WINPNSGSTNYAQKFQG 220 3510 1542 TGGATCAACCCTAACAGTGGTTCCACAAACTATGCACAGAAGTTTCAGG GC 220 3511 1543 ASRSWDHDAFDI 220 3512 1544 GCGAGCAGGAGCTGGGACCATGATGCTTTTGATATC 220 3513 1545 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGAGTAGCTCCAACATCGGGGCAGGTTA TGATGTACACTGGTACCAGCAGCTTCCAGGAAGAGCCCCCAAACTCCTC ATCTTTGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGCCTG AGGATGAGGCTGATTATTACTGCCACTGCTATGACAGCAGGCTGAGTGT GGTCTTCGGCGGAGGGACCAAGCTCACCGTCCTA 220 3514 1546 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGRAPKLLIFG NSNRPSGVPDRFSGSKSGTSASLAITGLQPEDEADYYCHCYDSRLSVVFGGG TKLTVL 220 3515 1547 TGSSSNIGAGYDVH 220 3516 1548 ACTGGGAGTAGCTCCAACATCGGGGCAGGTTATGATGTACAC 220 3517 1549 GNSNRPS 220 3518 1550 GGTAACAGCAATCGGCCCTCA 220 3519 1551 HCYDSRLSVV 220 3520 1552 CACTGCTATGACAGCAGGCTGAGTGTGGTC 221 3521 1553 CAGGTCCAGCTGGTACAGTCTGGGACTGAGGTGAAGAAGCCTGGGTCTT CGGTGAAGGTCTCCTGCAAGGCTTCGGGAGGCACCTTCAGTAGCTATGC TATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA GGGATCCACCCTACCTCTGGTCCAGCAAATTACGCACAGAAGTTCCAGG ATAGAGTCACCATTACCGTGGACAAGTCCACGAGCACAGTCTACATGGA CCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGA GTTGGTGTGGGTCGCACTTGGATATATGATACAATGGGTTACCTTGACTT CTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 221 3522 1554 QVQLVQSGTEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGG IHPTSGPANYAQKFQDRVTITVDKSTSTVYMDLSSLRSEDTAVYYCARVGV GRTWIYDTMGYLDFWGQGTLVTVSS 221 3523 1555 GTFSSYAIS 221 3524 1556 GGCACCTTCAGTAGCTATGCTATCAGC 221 3525 1557 GIHPTSGPANYAQKFQD 221 3526 1558 GGGATCCACCCTACCTCTGGTCCAGCAAATTACGCACAGAAGTTCCAGG AT 221 3527 1559 ARVGVGRTWIYDTMGYLDF 221 3528 1560 GCGAGAGTTGGTGTGGGTCGCACTTGGATATATGATACAATGGGTTACC TTGACTTC 221 3529 1561 GAAATTGTGATGACACAGTCTCCAGCCACGCTGTCTTTGTCTCCAGGAGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCGACTACTTA GCCTGGTACCAACAAAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCACCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCACCGTAGCGACTGGCCTTCCCTCACTTTC GGCGGAGGGACCAAGCTGGAGATCAAA 221 3530 1562 EIVMTQSPATLSLSPGERATLSCRASQSVSDYLAWYQQKPGQAPRLLIYDAS NRATGIPARFSGSGSGTDFTLTITSLEPEDFAVYYCQHRSDWPSLTFGGGTKL EIK 221 3531 1563 RASQSVSDYLA 221 3532 1564 AGGGCCAGTCAGAGTGTTAGCGACTACTTAGCC 221 3533 1565 DASNRAT 221 3534 1566 GATGCATCCAACAGGGCCACT 221 3535 1567 QHRSDWPSLT 221 3536 1568 CAGCACCGTAGCGACTGGCCTTCCCTCACT 222 3537 1569 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGT CCCTGAGACTCTCCTGTGTAACTTCGGGATTCGGCTTTGATGACTATGCC ATGCACTGGGTCCGGCAAGCCCCAGGGAAGGGCCTGGAGTGGGTCTCAG GGATTGGTTGGAATAGTGGTGGCATAGGCTATGCGGACTCTGTGAAGGG CCGATTCTCCATCTCCAGAGACAACGCCAAGAACTCCTTGTATCTACAAA TGAACAGTCTGAGACCTGAAGACACTGCCTTCTATTACTGTGTAAAAGA TGGGACCCCTATAGCAGTGGCTGGATACTTTGAATACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 222 3538 1570 EVQLVESGGGLVQPGRSLRLSCVTSGFGFDDYAMHWVRQAPGKGLEWVS GIGWNSGGIGYADSVKGRFSISRDNAKNSLYLQMNSLRPEDTAFYYCVKDG TPIAVAGYFEYWGQGTLVTVSS 222 3539 1571 FGFDDYAMH 222 3540 1572 TTCGGCTTTGATGACTATGCCATGCAC 222 3541 1573 GIGWNSGGIGYADSVKG 222 3542 1574 GGGATTGGTTGGAATAGTGGTGGCATAGGCTATGCGGACTCTGTGAAGG GC 222 3543 1575 VKDGTPIAVAGYFEY 222 3544 1576 GTAAAAGATGGGACCCCTATAGCAGTGGCTGGATACTTTGAATAC 222 3545 1577 TCCTATGAGCTGACACAGCCGCCCTCAGCGTCTGGTACCCCCGGGCAGA GGGTCACCATCTCTTGTTCTGGAGGCAGGTCCAACATCGGAAATAATTAT GTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCT ATAGGCATGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC AAGTCTGGCACCTCAGCCTCCCTGGCCATCAATGGGCTCCGGTCCGAGG ATGAGGCTGACTATTTTTGCGCAGTATGGGATGACAGCCTGAGTTGTTAT GTCTTCGGAGCTGGGACCAAGCTCACCGTCCTA 222 3546 1578 SYELTQPPSASGTPGQRVTISCSGGRSNIGNNYVYWYQQLPGTAPKLLIYRH DQRPSGVPDRFSGSKSGTSASLAINGLRSEDEADYFCAVWDDSLSCYVFGA GTKLTVL 222 3547 1579 SGGRSNIGNNYVY 222 3548 1580 TCTGGAGGCAGGTCCAACATCGGAAATAATTATGTATAC 222 3549 1581 RHDQRPS 222 3550 1582 AGGCATGATCAGCGGCCCTCA 222 3551 1583 AVWDDSLSCYV 222 3552 1584 GCAGTATGGGATGACAGCCTGAGTTGTTATGTC 223 3553 1585 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGCACCTATGG TATCAGCTGGGTGCGACAGGCCCCTGGACAAGGTCTTGAGTGGATGGGA AGGGTCATCCCTATGTTTGGAACAGCAACCTACGCACAGAAGTTCCAGG ACAGAGTCACGATTACCGCGGACAAAGCCACGAGCACGGCGTACATGG AGCTGAACAGCCTGAGATCTGACGACACGGCCGTATATTACTGTGCGAG ATGTCCTCCTTTTGAGGGAGTTCGTCCGCCCTGGTTCGACCCCTGGGGCC AGGGAACCCTGGTCACCGTCTCTTCA 223 3554 1586 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYGISWVRQAPGQGLEWMGR VIPMFGTATYAQKFQDRVTITADKATSTAYMELNSLRSDDTAVYYCARCPP FEGVRPPWFDPWGQGTLVTVSS 223 3555 1587 GTFSTYGIS 223 3556 1588 GGCACCTTCAGCACCTATGGTATCAGC 223 3557 1589 RVIPMFGTATYAQKFQD 223 3558 1590 AGGGTCATCCCTATGTTTGGAACAGCAACCTACGCACAGAAGTTCCAGG AC 223 3559 1591 ARCPPFEGVRPPWFDP 223 3560 1592 GCGAGATGTCCTCCTTTTGAGGGAGTTCGTCCGCCCTGGTTCGACCCC 223 3561 1593 TCCTATGAGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACGGA CGGCCAAGATTACCTGTGGGGGATACAACATTGGAAATAAACGTGTGCA CTGGTACCGGCAGAGGCCAGGCCAGGCCCCAGTGCTGATCGTCTATGAT AATGCCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTC TGGGAACACGGCCACCCTGACCATCAGCAACGTCGCAGCCGGGGATGAG GCCGACTATCACTGTCAGGTGTGGGAAACTAGTAGTGATCATCCGGTAT TCGGCGGAGGGACCAAGCTCACCGTCCTA 223 3562 1594 SYELTQPPSVSVAPGRTAKITCGGYNIGNKRVHWYRQRPGQAPVLIVYDNA DRPSGIPERFSGSNSGNTATLTISNVAAGDEADYHCQVWETSSDHPVFGGGT KLTVL 223 3563 1595 GGYNIGNKRVH 223 3564 1596 GGGGGATACAACATTGGAAATAAACGTGTGCAC 223 3565 1597 DNADRPS 223 3566 1598 GATAATGCCGACCGGCCCTCA 223 3567 1599 QVWETSSDHPV 223 3568 1600 CAGGTGTGGGAAACTAGTAGTGATCATCCGGTA 224 3569 1601 GAGGTGCAGCTGGTGCAGTCTGGAACAGAGGTGAAAAAGCCCGGGGAA TCTCTGAAGATCTCTTGTAAGGCTTCTGGATACAGCTCTTTCCCCAATTG GATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTACATGGG GTCCATCTITCCTGATGACTCTAATACCAGATATAGTCCGTCCTTCCGAG GCCTGGTCGCCATCTCAGCCGACAAGTCCCTGAGAACCGCCTATCTGCA GTGGAGCAGCCTGAAGGCCTCGGACAGCGCCATATATTACTGTGCGAGA GGGCCCTTCCCGCACTACTTTGACTCCTGGGGTCAGGGAACCCTGGTCAC CGTCTCCTCA 224 3570 1602 EVQLVQSGTEVKKPGESLKISCKASGYSSFPNWIGWVRQMPGKGLEYMGSI FPDDSNTRYSPSFRGLVAISADKSLRTAYLQWSSLKASDSAIYYCARGPFPH YFDSWGQGTLVTVSS 224 3571 1603 YSSFPNWIG 224 3572 1604 TACAGCTCTTTCCCCAATTGGATCGGC 224 3573 1605 SIFPDDSNTRYSPSFRG 224 3574 1606 TCCATCTTTCCTGATGACTCTAATACCAGATATAGTCCGTCCTTCCGAGG C 224 3575 1607 ARGPFPHYFDS 224 3576 1608 GCGAGAGGGCCCTTCCCGCACTACTTTGACTCC 224 3577 1609 AATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGAC GGTCACCATCTCCTGCACCCGCAGCAGTGGCAGTATTGCCCGCAACTAT GTGCAGTGGTACCAGCAGCGCCCGGGCAGTTCCCCCACCACTGTGATCT ATGAGGATGACCAAAGACCCCCTGGGGTCCCTGATCGGTTCTCTGGCTC CATCGACAGCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGCAGA CTGAGGACGAGGCTGACTACTACTGTCAGTCTTATGATCCCACCAATCA AAATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 224 3578 1610 NFMLTQPHSVSESPGKTVTISCTRSSGSIARNYVQWYQQRPGSSPTTVIYEDD QRPPGVPDRFSGSIDSSSNSASLTISGLQTEDEADYYCQSYDPTNQNVFGTGT KLTVL 224 3579 1611 TRSSGSIARNYVQ 224 3580 1612 ACCCGCAGCAGTGGCAGTATTGCCCGCAACTATGTGCAG 224 3581 1613 EDDQRPP 224 3582 1614 GAGGATGACCAAAGACCCCCT 224 3583 1615 QSYDPTNQNV 224 3584 1616 CAGTCTTATGATCCCACCAATCAAAATGTC 225 3585 1617 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGAAGCCTCTGGATTCAACTTCCATAATTATGAT ATACAATGGGTCCGCCAGGCCCCAGGCAAGGGGCTGGAGTGGGTGGCA CTAGTATTATTTGATGGAAGCAAAAAATATTATCCACACTCTGTGAAGG GCCGATTCGCCATCTCCAGAGACAACTCCAAAAAAACTCTATTTCTGCA AATGAACAGCCTGAGACCTGAGGACACGGCTGTGTATTACTGTGCGAGA GCCCCAGTGACTGGCGCCTCGTATTACCTTGACTATTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCA 225 3586 1618 EVQLVESGGGVVQPGRSLRLSCEASGFNFHNYDIQWVRQAPGKGLEWVAL VLFDGSKKYYPHSVKGRFAISRDNSKKTLFLQMNSLRPEDTAVYYCARAPV TGASYYLDYWGQGTLVTVSS 225 3587 1619 FNFHNYDIQ 225 3588 1620 TTCAACTTCCATAATTATGATATACAA 225 3589 1621 LVLFDGSKKYYPHSVKG 225 3590 1622 CTAGTATTATTTGATGGAAGCAAAAAATATTATCCACACTCTGTGAAGG GC 225 3591 1623 ARAPVTGASYYLDY 225 3592 1624 GCGAGAGCCCCAGTGACTGGCGCCTCGTATTACCTTGACTAT 225 3593 1625 TCCTATGTGCTGACACAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGA CGGCCAGAATTACCTGTGGGGCAAACAACATTGGAAATAAAGGTGTGCA CTGGTACCAACAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTCTATGAT GATGACGACCAGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACT CTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAGCCGGGGATG AGGCCGACTATTACTGTCAGGTGTGGGATAGTACTAGTGATCATCTGGT ATTCGGCGGAGGGACCCAGCTGACCGTCCTA 225 3594 1626 SYVLTQPPSVSVAPGQTARITCGANNIGNKGVHWYQQKPGQAPVLVVYDD DDQPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSTSDHLVFGG GTQLTVL 225 3595 1627 GANNIGNKGVH 225 3596 1628 GGGGCAAACAACATTGGAAATAAAGGTGTGCAC 225 3597 1629 DDDDQPS 225 3598 1630 GATGATGACGACCAGCCCTCA 225 3599 1631 QVWDSTSDHLV 225 3600 1632 CAGGTGTGGGATAGTACTAGTGATCATCTGGTA 226 3601 1633 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGA CCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCGTCAGCAGAGGGAGT TACTACTGGACCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA TTGGCTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCAAG AGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTTTATTACTGTGCGAG AGATATAGGGGAAGATAAGTATGGTACTTACTACGGTATGGACGTCTGG GGCCAAGGGACCACGGTCACCGTCTCTTCA 226 3602 1634 QVQLQESGPGLVKPSETLSLTCTVSGGSVSRGSYYWTWIRQPPGKGLEWIG YIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDIGE DKYGTYYGMDVWGQGTTVTVSS 226 3603 1635 GSVSRGSYYWT 226 3604 1636 GGCTCCGTCAGCAGAGGGAGTTACTACTGGACC 226 3605 1637 YIYYSGSTNYNPSLKS 226 3606 1638 TATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGT 226 3607 1639 ARDIGEDKYGTYYGMDV 226 3608 1640 GCGAGAGATATAGGGGAAGATAAGTATGGTACTTACTACGGTATGGACG TC 226 3609 1641 GAAATTGTGATGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGAGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTCCTTA GCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG GTGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGTAGCCTAGAGCCTGAGGAT TTTGCAGTTTATTACTGTCAGCAGCGTACCAACTGGCCCCCGGTCACTTT CGGCCCTGGGACCAAGGTGGAAATCAAA 226 3610 1642 EIVMTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYGAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRTNWPPVTFGPGTKV EIK 226 3611 1643 RASQSVSSSLA 226 3612 1644 AGGGCCAGTCAGAGTGTTAGCAGCTCCTTAGCC 226 3613 1645 GASNRAT 226 3614 1646 GGTGCATCCAACAGGGCCACT 226 3615 1647 QQRTNWPPVT 226 3616 1648 CAGCAGCGTACCAACTGGCCCCCGGTCACT 227 3617 1649 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATACC ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCACAAACTACGCAGACTCACTGGAGGG CCGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAA TGAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGA TCAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 227 3618 1650 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYTMNWVRQAPGKGLEWVSS ITGGSSFTNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 227 3619 1651 FTFSSYTMN 227 3620 1652 TTCACCTTCAGTAGCTATACCATGAAC 227 3621 1653 SITGGSSFTNYADSLEG 227 3622 1654 TCCATTACTGGTGGTAGTAGTTTCACAAACTACGCAGACTCACTGGAGG GC 227 3623 1655 ARDQPGTIFGVVQDY 227 3624 1656 GCGAGAGATCAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTAC 227 3625 1657 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCGCCTGAGTGT GGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 227 3626 1658 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGAGYDVHWYQQLPGTAPKLLIYG NSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLSVVFGGG TKVTVL 227 3627 1659 TGGSSNIGAGYDVH 227 3628 1660 ACTGGGGGCAGCTCCAACATCGGGGCAGGTTATGATGTGCAC 227 3629 1661 GNSNRPS 227 3630 1662 GGTAACAGCAATCGGCCCTCA 227 3631 1663 QSYDSRLSVV 227 3632 1664 CAGTCCTATGACAGCCGCCTGAGTGTGGTA 228 3633 1665 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGC TATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGA GGGACCATCCCTATTTTTGGTACAATCAACTACGCACAGAAGTTCCAGG GCAGACTCACGATTAACGCGGACGCATCAACGAGCACAGCCTACATGGA GCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTTCTGTGCGAGA GACCGGACTACAGCTGTGAGGTACTACGCTATGGACGTCTGGGGCCAAG GGACCACGGTCACCGTCTCTTCA 228 3634 1666 EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGG TIPIFGTINYAQKFQGRLTINADASTSTAYMELSSLRSEDTAVYFCARDRTTA VRYYAMDVWGQGTTVTVSS 228 3635 1667 GTFSSYAIS 228 3636 1668 GGCACCTTCAGCAGCTATGCTATCAGC 228 3637 1669 GTIPIFGTINYAQKFQG 228 3638 1670 GGGACCATCCCTATTTTTGGTACAATCAACTACGCACAGAAGTTCCAGG GC 228 3639 1671 ARDRTTAVRYYAMDV 228 3640 1672 GCGAGAGACCGGACTACAGCTGTGAGGTACTACGCTATGGACGTC 228 3641 1673 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTA GCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATACATCCAACAGGGCCACTGACATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCACCGTGCCAACTGGCCCCCGCTCACTTT CGGCGGAGGGACCAAGGTGGAAATCAAA 228 3642 1674 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDTSN RATDIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHRANWPPLTFGGGTKV EIK 228 3643 1675 RASQSVSSYLA 228 3644 1676 AGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCC 228 3645 1677 DTSNRAT 228 3646 1678 GATACATCCAACAGGGCCACT 228 3647 1679 QHRANWPPLT 228 3648 1680 CAGCACCGTGCCAACTGGCCCCCGCTCACT 229 3649 1681 CAGGTCCAGCTTGTGCAGTCTGGGCCTGAGGTGAAGAGGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGACACCTTCAACAACTACGC CATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGA GGGATCCACCCTACCACTGCTACACCAAACTACGCACAGAAGTTCCAGG GCAGAGTCGTCATTAGCGCGGACAAGTCCACGAGTACAGCCTACTTGGA CCTGAGTCGGCTGAGATCTGAGGACACGGCCATGTATTACTGTGCGAGA GTTGGTGTGGGACGCACTTGGGTCTATGATATTATGGGTTACCTAGACTA CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 229 3650 1682 QVQLVQSGPEVKRPGSSVKVSCKASGDTFNNYAISWVRQAPGQGLEWMGG IHPTTATPNYAQKFQGRVVISADKSTSTAYLDLSRLRSEDTAMYYCARVGV GRTWVYDIMGYLDYWGQGTLVTVSS 229 3651 1683 DTFNNYAIS 229 3652 1684 GACACCTTCAACAACTACGCCATCAGC 229 3653 1685 GIHPTTATPNYAQKFQG 229 3654 1686 GGGATCCACCCTACCACTGCTACACCAAACTACGCACAGAAGTTCCAGG GC 229 3655 1687 ARVGVGRTWVYDIMGYLDY 229 3656 1688 GCGAGAGTTGGTGTGGGACGCACTTGGGTCTATGATATTATGGGTTACCT AGACTAC 229 3657 1689 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCGACTACTTG GCCTGGTACCAACAAAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCGTCCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCGGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAACACCGTAACAACTGGCCTTCCCTCACTTTC GGCGGAGGGACCAAGGTGGAAATCAAA 229 3658 1690 EIVLTQSPATLSLSPGERATLSCRASQSVSDYLAWYQQRPGQAPRLLIYDAS TRATGIPDRFSGGGSGTDFTLTISSLEPEDFAVYYCQHRNNWPSLTFGGGTK VEIK 229 3659 1691 RASQSVSDYLA 229 3660 1692 AGGGCCAGTCAGAGTGTTAGCGACTACTTGGCC 229 3661 1693 DASTRAT 229 3662 1694 GATGCGTCCACCAGGGCCACT 229 3663 1695 QHRNNWPSLT 229 3664 1696 CAACACCGTAACAACTGGCCTTCCCTCACT 230 3665 1697 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGCTGAAGCCTTCGGAGA CCCTGTCCCTCACCTGCGGTGTCTCTGATGGGTCCTTCAGTGCCTACTAC TGGAACTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGGATTGGGG AAACCAATCCAAGTGAAAACACCAACTACAGCCCGTCCCTCAAGAATCG AGTCACCATATCGGCAGACAGGTCCGCGAATCAGTTCTCCCTGAGACTG AGGTCTGTGACCGCCGCGGACACGGGTGTTTATTACTGTGCGAGAGGCC GCGGTTATTATGGTTCGACGACTGATTATCGGGGGCTCCACTGGTTCGAC CCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 230 3666 1698 QVQLQQWGAGLLKPSETLSLTCGVSDGSFSAYYWNWIRQSPGKGLEWIGE TNPSENTNYSPSLKNRVTISADRSANQFSLRLRSVTAADTGVYYCARGRGY YGSTTDYRGLHWFDPWGQGTLVTVSS 230 3667 1699 GSFSAYYWN 230 3668 1700 GGGTCCTTCAGTGCCTACTACTGGAAC 230 3669 1701 ETNPSENTNYSPSLKN 230 3670 1702 GAAACCAATCCAAGTGAAAACACCAACTACAGCCCGTCCCTCAAGAAT 230 3671 1703 ARGRGYYGSTTDYRGLHWFDP 230 3672 1704 GCGAGAGGCCGCGGTTATTATGGTTCGACGACTGATTATCGGGGGCTCC ACTGGTTCGACCCC 230 3673 1705 GAAACGACACTCACGCAGTCTCCAGTCACCCTGTCTGTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCTTCAACTT AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GGTGCATCCACCAGGGTCACTAATCTCCCACTCAGGTTCAGTGGCAGTG GGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGA TTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCTCGGACTTTTG GCCAGGGGACCAAGCTGGAGATCAAA 230 3674 1706 ETTLTQSPVTLSVSPGERATLSCRASQSVSFNLAWYQQKPGQAPRLLIYGAS TRVTNLPLRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPRTFGQGTKL EIK 230 3675 1707 RASQSVSFNLA 230 3676 1708 AGGGCCAGTCAGAGTGTTAGCTTCAACTTAGCC 230 3677 1709 GASTRVT 230 3678 1710 GGTGCATCCACCAGGGTCACT 230 3679 1711 QQYNNWPRT 230 3680 1712 CAGCAGTATAATAACTGGCCTCGGACT 231 3681 1713 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCGGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGCGACTTTTCC ATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAC TTATTAAAAGTAGCGGTTATGCATACTATGCAGACTCCGTGAGGGGCCG GTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATG AACAGCCTGAGAGCCGAGGACACGGCCATATATTATTGTGCGAAAGACG CCGATTTTTGGAGTGGTGCCGCCTACAATGGAGGATACAACTTTGACTCC TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 231 3682 1714 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFSMSWVRQAPGKGLEWVSLI KSSGYAYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCAKDADF WSGAAYNGGYNFDSWGQGTLVTVSS 231 3683 1715 FTFSDFSMS 231 3684 1716 TTCACTTTCAGCGACTTTTCCATGAGC 231 3685 1717 LIKSSGYAYYADSVRG 231 3686 1718 CTTATTAAAAGTAGCGGTTATGCATACTATGCAGACTCCGTGAGGGGC 231 3687 1719 AKDADFWSGAAYNGGYNFDS 231 3688 1720 GCGAAAGACGCCGATTTTTGGAGTGGTGCCGCCTACAATGGAGGATACA ACTTTGACTCC 231 3689 1721 GACATCCAGATGACCCAGTCTCCAGCCACCCTGTCTGTATTTCCAGGGGA CAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAACTTG GCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTTTG GTGCCTCAACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGTATCATAACTGGCCTCCGCTCACTTTC GGCGGAGGGACCAAAGTGGATATCAAA 231 3690 1722 DIQMTQSPATLSVFPGDRATLSCRASQSVGSNLAWYQQKPGQAPRLLIFGAS TRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYFINWPPLTFGGGTK VDIK 231 3691 1723 RASQSVGSNLA 231 3692 1724 AGGGCCAGTCAGAGTGTTGGCAGCAACTTGGCC 231 3693 1725 GASTRAT 231 3694 1726 GGTGCCTCAACCAGGGCCACT 231 3695 1727 QQYFINWPPLT 231 3696 1728 CAGCAGTATCATAACTGGCCTCCGCTCACT 232 5905 1729 CAGGTCCAGCTTGTACAGTCTGGGGCTGAAGTGAAGAGGCCTGGGTCCT (ADI- CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTTTGG 31672) GATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA GGGCTCAATCCTATCTTTGGTACACCATCTAACGCACAGAAGTTCCAGG GCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGA GCTGAGCAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTGCCTCA TTACGATATTTTGACTGGCAACCTGGGGGGTCCTACTGGTTCGACCCCTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCA 5906 1730 QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSFGINWVRQAPGQGLEWMGG LNPIFGTPSNAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCASLRYF DWQPGGSYWFDPWGQGTLVTVSS 5907 1731 GTFSSFGIN 5908 1732 GLNPIFGTPSNAQKFQG 5909 1733 ASLRYFDWQPGGSYWFDP 5910 1734 CAGCCTGGGCTGACTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAAGA CGGCCAGGATTGCCTGTGGGGGAGACAACATTGGAACTAAAGGAGTGC ACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCATCTATTA TGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGTTCCAACT CTGGGAACACGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATG AGGCCGACTACTACTGTCAGGTTTGGGATACTATTGATGATTATAAGGAT GGACTATTCGGCGGAGGGACCAAGCTCACCGTCCTA 5911 1735 QPGLTQPPSVSVAPGKTARIACGGDNIGTKGVHWYQQKPGQAPVLVIYYDS DRPSGIPERFSGSNSGNTATLTISGVEAGDEADYYCQVWDTIDDYKDGLFGG GTKLTVL 5912 1736 GGDNIGTKGVH 5913 1737 YDSDRPS 5914 1738 QVWDTIDDYKDGL 233 5915 1739 CAGGTCCAGCTTGTACAGTCTGGGGCTGAAGTGAAGAGGCCTGGGTCCT (ADI- CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTTTGCT 31673) ATCCAGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG GGCTCATCCCTATCTTTGGTACACCAGAGAACGCACAGAAGTTCCAGGG CAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAG CTGAGCAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTGCCTCATT ACGATATTTTGACTGGCAACCTGGGGGGTCCTACTGGTTCGACCCCTGGG GCCAGGGAACCCTGGTCACCGTCTCCTCA 5916 1740 QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSFAIQWVRQAPGQGLEWMGG LIPIFGTPENAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCASLRYFD WQPGGSYWFDPWGQGTLVTVSS 5917 1741 GTFSSFAIQ 5918 1742 GLIPIFGTPENAQKFQG 5919 1743 ASLRYFDWQPGGSYWFDP 5920 1744 CAGCCTGGGCTGACTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAAGA CGGCCAGGATTGCCTGTGGGGGAGACAACATTGGAACTAAAGGAGTGC ACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCATCTATTA TGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGTTCCAACT CTGGGAACACGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATG AGGCCGACTACTACTGTCAGGTTTGGGATACTATTGATGATCATAAGGA TGGACTATTCGGCGGAGGGACCAAGCTCACCGTCCTA 5921 1745 QPGLTQPPSVSVAPGKTARIACGGDNIGTKGVHWYQQKPGQAPVLVIYYDS DRPSGIPERFSGSNSGNTATLTISGVEAGDEADYYCQVWDTIDDHKDGLFGG GTKLTVL 5922 1746 GGDNIGTKGVH 5923 1747 YDSDRPS 5924 1748 QVWDTIDDHKDGL 234 5925 1749 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT (ADI- CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTTTTCT 31674) ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAC TCATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGGG TTCATTCATCATCTCCAGAGACAACTCCAAGAACACGCTCTATCTCCAAC TGAACAGCCTGGGAGCTGAGGACACGGCTCTCTATTACTGTGCGAGAGA TGCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACTACTGGGGCC AGGGAACCCTGGTCACTGTCTCCTCA 5926 1750 EVQLLESGGGVVQPGRSLRLSCAASGFTFSDFSMHWVRQAPGKGLEWVALI SNDGSNKYYSDSLKGSFIISRDNSKNTLYLQLNSLGAEDTALYYCARDAVPH YDYVWGNFDYWGQGTLVTVSS 5927 1751 FTFSDFSMH 5928 1752 LISNDGSNKYYSDSLKG 5929 1753 ARDAVPHYDYVWGNFDY 5930 1754 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTTTTCT ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAC TCATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGGG TTCATTCATCATCTCCAGAGACAACTCCAAGAACACGCTCTATCTCCAAC TGAACAGCCTGGGAGCTGAGGACACGGCTCTCTATTACTGTGCGAGAGA TGCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACTACTGGGGCC AGGGAACCCTGGTCACTGTCTCCTCA 5931 1755 EVQLLESGGGVVQPGRSLRLSCAASGFTFSDFSMHWVRQAPGKGLEWVALI SNDGSNKYYSDSLKGSFIISRDNSKNTLYLQLNSLGAEDTALYYCARDAVPH YDYVWGNFDYWGQGTLVTVSS 5932 1756 TGTASDVGGYNYVS 5933 1757 EVSNRPS 5934 1758 SSYTSFTPVV 235 5935 1759 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT (ADI- CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTTTTCT 31674S ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAC 95A) TCATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGGG TTCATTCATCATCTCCAGAGACAACTCCAAGAACACGCTCTATCTCCAAC TGAACAGCCTGGGAGCTGAGGACACGGCTCTCTATTACTGTGCGAGAGA TGCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACTACTGGGGCC AGGGAACCCTGGTCACTGTCTCCTCA 5936 1760 EVQLLESGGGVVQPGRSLRLSCAASGFTFSDFSMHWVRQAPGKGLEWVALI SNDGSNKYYSDSLKGSFIISRDNSKNTLYLQLNSLGAEDTALYYCARDAVPH YDYVWGNFDYWGQGTLVTVSS 5937 1761 FTFSDFSMH 5938 1762 LISNDGSNKYYSDSLKG 5939 1763 ARDAVPHYDYVWGNFDY 5940 1764 CAGTCTGTTCTGACTCAGCCTGCCTCCGTGTCTGCGTCTCCTGGACAGTC GATCACCATCTCCTGCACTGGAACCGCGAGTGACGTTGGTGGTTATAATT ATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATAAT TTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA CGACGAGGCTGATTATTACTGCAGCTCATATACAGCTTTCACTCCCGTGG TATTCGGCGGAGGGACCAAGCTGACCGTCCTA 5941 1765 QSVLTQPASVSASPGQSITISCTGTASDVGGYNYVSWYQQHPGKAPKLIIYE VSNRPSGVSNRFSGSKSGNTASLTISGLQADDEADYYCSSYTAFTPVVFGGG TKLTVL 5942 1766 TGTASDVGGYNYVS 5943 1767 EVSNRPS 5944 1768 SSYTAFTPVV 236 5945 1769 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT (ADI- CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTTTTCT 31675) ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAC TCATCTCAAATGATGGAAGCAATAAATATTATTCAGACTCCCTGAAGGG TTCATTCATCATCTCCAGAGACAACTCCAAGAACACGCTCTATCTCCAAC TGAACAGCCTGGGAGCTGAGGACACGGCTCTCTATTACTGTGCGAGAGA TGCGGTTCCCCATTATGATTACGTCTGGGGAAACTTTGACTACTGGGGCC AGGGAACCCTGGTCACTGTCTCCTCA 5946 1770 EVQLLESGGGVVQPGRSLRLSCAASGFTFSDFSMHWVRQAPGKGLEWVALI SNDGSNKYYSDSLKGSFIISRDNSKNTLYLQLNSLGAEDTALYYCARDAVPH YDYVWGNFDYWGQGTLVTVSS 5947 1771 FTFSDFSMH 5948 1772 LISNDGSNKYYSDSLKG 5949 1773 ARDAVPHYDYVWGNFDY 5950 1774 CAGTCTGTTCTGACTCAGCCTGCCTCCGTGTCTGCGTCTCCTGGACAGTC GATCACCATCTCCTGCACTGGAACCGCGAGTGACGTTGGTGGTTATAATT ATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATAAT TTATGAGAAGAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCT CCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGA CGACGAGGCTGATTATTACTGCAGCTCATATACAAGTTTCACTCCCGTGG TATTCGGCGGAGGGACCAAGCTGACCGTCCTA 5951 1775 QSVLTQPASVSASPGQSITISCTGTASDVGGYNYVSWYQQHPGKAPKLIIYE KSNRPSGVSNRFSGSKSGNTASLTISGLQADDEADYYCSSYTSFTPVVFGGG TKLTVL 5952 1776 TGTASDVGGYNYVS 5953 1777 EKSNRPS 5954 1778 SSYTSFTPVV 237 5955 1779 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATACC 31378) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCACAAACTACGCAGACTCACTGGAGGG CCGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAA TGAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGA TCAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 5956 1780 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYTMNWVRQAPGKGLEWVSS ITGGSSFTNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 5957 1781 FTFSSYTMN 5958 1782 SITGGSSFTNYADSLEG 5959 1783 ARDQPGTIFGVVQDY 5960 1784 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCTAAACTCCTC ATCTATGGTAACAGCAATCGGGGGTCAGGGGTCCCTGACCGATTCTCTG GCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCT GAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCGCCTGCAGG TGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5961 1785 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGAGYDVHWYQQLPGTAPKLLIYG NSNRGSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLQVVFGG GTKVTVL 5962 1786 TGGSSNIGAGYDVH 5963 1787 GNSNRGS 5964 1788 QSYDSRLQVV 238 5965 1789 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATACC 31379) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCACAAACTACGCAGACTCACTGGAGGG CCGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAA TGAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGA TCAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 5966 1790 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYTMNWVRQAPGKGLEWVSS ITGGSSFTNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 5967 1791 FTFSSYTMN 5968 1792 SITGGSSFTNYADSLEG 5969 1793 ARDQPGTIFGVVQDY 5970 1794 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGAAGGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAGCAATCGGCCCGGGGGGGTCCCTGACCGATTCTCTG GCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCT GAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCGGGCTGAGTG TGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5971 1795 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGKGYDVHWYQQLPGTAPKLLIYG NSNRPGGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSGLSVVFGG GTKVTVL 5972 1796 TGGSSNIGKGYDVH 5973 1797 GNSNRPG 5974 1798 QSYDSGLSVV 239 5975 1799 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCAAGTTCAGTAGCTATACC 31380) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCACAAACTACGCAGACTCACTGGAGGG CCGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAA TGAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGA TCAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 5976 1800 QVQLVQSGGGLVKPGGSLRLSCAASGFKFSSYTMNWVRQAPGKGLEWVSS ITGGSSFTNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 5977 1801 FKFSSYTMN 5978 1802 SITGGSSFTNYADSLEG 5979 1803 ARDQPGTIFGVVQDY 5980 1804 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCGCCTGAGTGT GGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5981 1805 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGAGYDVHWYQQLPGTAPKLLIYG NSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLSVVFGGG TKVTVL 5982 1806 TGGSSNIGAGYDVH 5983 1807 GNSNRPS 5984 1808 QSYDSRLSVV 240 5985 1809 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCAGCTTCAGTAGCTATAGC 31381) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCGTTAACTACGCAGACTCACTGGAGGGC CGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAAT GAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGAT CAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCA 5986 1810 QVQLVQSGGGLVKPGGSLRLSCAASGFSFSSYSMNWVRQAPGKGLEWVSSI TGGSSFVNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 5987 1811 FSFSSYSMN 5988 1812 SITGGSSFVNYADSLEG 5989 1813 ARDQPGTIFGVVQDY 5990 1814 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGG CTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTG AGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCGCCTGAGTGT GGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 5991 1815 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGAGYDVHWYQQLPGTAPKLLIYG NSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLSVVFGGG TKVTVL 5992 1816 TGGSSNIGAGYDVH 5993 1817 GNSNRPS 5994 1818 QSYDSRLSVV 241 5995 1819 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCAAGTTCAGTAGCTATACC 31312) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCACAAACTACGCAGACTCACTGGAGGG CCGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAA TGAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGA TCAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 5996 1820 QVQLVQSGGGLVKPGGSLRLSCAASGFKFSSYTMNWVRQAPGKGLEWVSS ITGGSSFTNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 5997 1821 FKFSSYTMN 5998 1822 SITGGSSFTNYADSLEG 5999 1823 ARDQPGTIFGVVQDY 6000 1824 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCTAAACTCCTC ATCTATGGTAACAGCAATCGGGGGTCAGGGGTCCCTGACCGATTCTCTG GCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCT GAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCGCCTGCAGG TGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 6001 1825 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGAGYDVHWYQQLPGTAPKLLIYG NSNRGSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLQVVFGG GTKVTVL 6002 1826 TGGSSNIGAGYDVH 6003 1827 GNSNRGS 6004 1828 QSYDSRLQVV 242 6005 1829 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCAAGTTCAGTAGCTATACC 31319) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCACAAACTACGCAGACTCACTGGAGGG CCGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAA TGAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGA TCAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA 6006 1830 QVQLVQSGGGLVKPGGSLRLSCAASGFKFSSYTMNWVRQAPGKGLEWVSS ITGGSSFTNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 6007 1831 FKFSSYTMN 6008 1832 SITGGSSFTNYADSLEG 6009 1833 ARDQPGTIFGVVQDY 6010 1834 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGAAGGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAGCAATCGGCCCGGGGGGGTCCCTGACCGATTCTCTG GCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCT GAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCGGGCTGAGTG TGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 6011 1835 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGKGYDVHWYQQLPGTAPKLLIYG NSNRPGGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSGLSVVFGG GTKVTVL 6012 1836 TGGSSNIGKGYDVH 6013 1837 GNSNRPG 6014 1838 QSYDSGLSVV 243 6015 1839 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCAGCTTCAGTAGCTATAGC 31328) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCGTTAACTACGCAGACTCACTGGAGGGC CGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAAT GAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGAT CAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCA 6016 1840 QVQLVQSGGGLVKPGGSLRLSCAASGFSFSSYSMNWVRQAPGKGLEWVSSI TGGSSFVNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 6017 1841 FSFSSYSMN 6018 1842 SITGGSSFVNYADSLEG 6019 1843 ARDQPGTIFGVVQDY 6020 1844 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGGTTA TGATGTGCACTGGTACCAGCAGAATCCAGGAACAGCCCCTAAACTCCTC ATCTATGGTAACAGCAATCGGGGGTCAGGGGTCCCTGACCGATTCTCTG GCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCT GAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCGCCTGCAGG TGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 6021 1845 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGAGYDVHWYQQNPGTAPKWYG NSNRGSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLQVVFGG GTKVTVL 6022 1846 TGGSSNIGAGYDVH 6023 1847 GNSNRGS 6024 1848 QSYDSRLQVV 244 6025 1849 CAGGTCCAGCTGGTACAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGT (ADI- CCCTGAGACTCTCTTGTGCAGCCTCTGGATTCAGCTTCAGTAGCTATAGC 31330) ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAT CCATTACTGGTGGTAGTAGTTTCGTTAACTACGCAGACTCACTGGAGGGC CGATTCACCATCTCCAGAGATAACGCCAAGAGCTCACTTTTTCTGCAAAT GAACAGCCTGAGAGTCGAGGACACGGCTGTATATTACTGTGCGAGAGAT CAGCCGGGGACGATTTTTGGAGTGGTCCAGGACTACTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCA 6026 1850 QVQLVQSGGGLVKPGGSLRLSCAASGFSFSSYSMNWVRQAPGKGLEWVSSI TGGSSFVNYADSLEGRFTISRDNAKSSLFLQMNSLRVEDTAVYYCARDQPG TIFGVVQDYWGQGTLVTVSS 6027 1851 FSFSSYSMN 6028 1852 SITGGSSFVNYADSLEG 6029 1853 ARDQPGTIFGVVQDY 6030 1854 CAGTCTGTCTTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGA GGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGAAGGGTTA TGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTC ATCTATGGTAACAGCAATCGGCCCGGGGGGGTCCCTGACCGATTCTCTG GCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCT GAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCGGGCTGAGTG TGGTATTCGGCGGAGGGACCAAGGTGACCGTCCTA 6031 1855 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGKGYDVHWYQQLPGTAPKLLIYG NSNRPGGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSGLSVVFGG GTKVTVL 6032 1856 TGGSSNIGKGYDVH 6033 1857 GNSNRPG 6034 1858 QSYDSGLSVV

Additional Embodiments

Embodiment 1. An isolated antibody or an antigen-binding fragment thereof that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics:

a) the antibody or antigen-binding fragment thereof cross-competes with said antibody or antigen-binding fragment thereof for binding to RSV-F;

b) the antibody or antigen-binding fragment thereof displays better binding affinity for the PreF form of RSV-F relative to the PostF form;

c) the antibody or antigen-binding fragment thereof displays a clean or low polyreactivity profile;

d) the antibody or antigen-binding fragment thereof displays neutralization activity toward RSV suptype A and RSV subtype B in vitro;

e) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F at Site Ø, Site I, Site II, Site III, Site IV, or Site V;

f) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV;

g) at least a portion of the epitope with which the antibody or antigen-binding fragment thereof interacts comprises the α3 helix and β3/β4 hairpin of PreF;

h) the antibody or antigen-binding fragment thereof displays an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml;

i) the binding affinity and/or epitopic specificity of the antibody or antigen-binding fragment thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1;

j) the antibody or antigen-binding fragment thereof of displays a cross-neutalization potency (IC₅₀) against human metapneumovirus (HMPV);

k) the antibody or antigen-binding fragment thereof does not complete with D25, MPEG, palivizumab, or motavizumab; or

l) the the antibody or antigen-binding fragment thereof displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.

Embodiment 2. The isolated antibody or antigen-binding fragment thereof of Embodiment 1, wherein the antibody or antigen-binding fragment thereof comprises: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through l).

Embodiment 3. The isolated antibody or antigen-binding fragment thereof of Embodiment 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises:

a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6;

b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6;

c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6;

d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6;

e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6;

f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; or

g) any combination of two or more of a), b), c), d), e), and f).

Embodiment 4. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 3, wherein the antibody or antigen-binding fragment thereof comprises:

a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; and/or

b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

Embodiment 5. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 4, wherein the antibody is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

Embodiment 6. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 5, wherein the antibody is selected from the group consisting of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table 6.

Embodiment 7. An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment thereof according to any one of Embodiments 1 through 6.

Embodiment 8. An expression vector comprising the isolated nucleic acid sequence according to Embodiment 7.

Embodiment 9. A host cell transfected, transformed, or transduced with the nucleic acid sequence according to Embodiment 7 or the expression vector according to Embodiment 8.

Embodiment 10. A pharmaceutical composition comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to any one of Embodiments 1 through 6; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 11. A pharmaceutical composition comprising: one or more nucleic acid sequences according to Embodiment 7; or one or more the expression vectors according to Embodiment 8; and a pharmaceutically acceptable carrier and/or excipient.

Embodiment 12. A transgenic organism comprising the nucleic acid sequence according to Embodiment 7; or the expression vector according to Embodiment 8.

Embodiment 13. A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments 1 through 6;

b) a nucleic acid sequences according to Embodiment 7;

c) an expression vector according to Embodiment 8;

d) a host cell according to Embodiment 9; or

e) a pharmaceutical composition according Embodiment 10 or Embodiment 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

Embodiment 14. A method of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments 1 through 6;

b) a nucleic acid sequences according to Embodiment 7;

c) an expression vector according to Embodiment 8;

d) a host cell according to Embodiment 9; or

e) a pharmaceutical composition according Embodiment 10 or Embodiment 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.

Embodiment 15. The method according to Embodiment 14, wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies desifgnated as Antibody Number 179, 188, 211, 221, or 229 as disclosed in Table 6.

Embodiment 16. The method according to any one of Embodiments 13 through 15, wherein the method further comprises administering to the patient a second therapeutic agent.

Embodiment 17. The method according to Embodiment 16, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.

Embodiment 18. A pharmacuetical composition comprising any one or more of the isolated antibodies or antigen-binding fragments thereof of any one of Embodiments 1 through 7 and a pharmaceutically acceptable carrier and/oror excipient.

Embodiment 19. The pharmaceutical composition according to Embodiment 18 for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment 20. The pharmaceutical composition according to Embodiment 18 for us in treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.

Embodiment 21. Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.

Embodiment 22. Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use. 

What is claimed is:
 1. An isolated antibody or an antigen-binding fragment thereor that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics: a) the antibody or antigen-binding fragment thereof cross-competes with said antibody ar antigen-binding fragment thereof for binding to RSV-F; b) the antibody or antigen-binding fragment thereof displays better binding affinity for the PreF form of RSV-F relative to the PostF form; c) the antibody or antigen-binding fragment thereof displays a clean or low polyreactivity profile; d) the antibody or antigen-binding fragment thereof displays neutralization activity towoard RSV suptype A and RSV subtype B in vitro; e) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F at Site Ø, Site I, Site II, Site III, Site IV, or Site V; f) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the antibody or antigen-binding fragment thereof interacts comprises the α3 helix and β3/β4 hairpin of PreF; h) the antibody or antigen-binding fragment thereof displays an in vitro neutralization potency (IC₅₀) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml; i) the binding affinity and/or epitopic specificity of the antibody or antigen-binding fragment thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1; j) the antibody or antigen-binding fragment thereof of displays a cross-neutalization potency (IC₅₀) against human metapneumovirus (HMPV); k) the antibody or antigen-binding fragment thereof does not complete with D25, MPEG, palivisumab, motavizumab, or AM-14; or l) the the antibody or antigen-binding fragment thereof displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.
 2. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through l).
 3. The isolated antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises: a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; or g) any combination of two or more of a), b), c), d), e), and f).
 4. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 through 3, wherein the antibody or antigen-binding fragment thereof comprises: a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table 6; and/or b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 124 through Antibody Number 244 as disclosed in Table
 6. 5. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 through 4, wherein the antibody is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table
 6. 6. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 through 5, wherein the antibody is selected from the group consisting of the antibodies designated as Antibody Number 124 through Antibody Number 244 as disclosed in Table
 6. 7. An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment thereof according to any one of claims 1 through
 6. 8. An expression vector comprising the isolated nucleic acid sequence according to claim
 7. 9. A host cell transfected, transformed, or transduced with the nucleic acid sequence according to claim 7 or the expression vector according to claim
 8. 10. A pharmaceutical composition comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to any one of claims 1 through 6; and a pharmaceutically acceptable carrier and/or excipient.
 11. A pharmaceutical composition comprising: one or more nucleic acid sequences according to claim 7; or one or more the expression vectors according to claim 8; and a pharmaceutically acceptable carrier and/or excipient.
 12. A transgenic organism comprising the nucleic acid sequence according to claim 7; or the expression vector according to claim
 8. 13. A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to any of claims 1 through 6; b) a nucleic acid sequences according to claim 7; c) an expression vector according to claim 8; d) a host cell according to claim 9; or e) a pharmaceutical composition according claim 10 or claim 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
 14. A method of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to any of claims 1 through 6; b) a nucleic acid sequences according to claim 7; c) an expression vector according to claim 8; d) a host cell according to claim 9; or e) a pharmaceutical composition according claim 10 or claim 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
 15. The method according to claim 14, wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies desifgnated as Antibody Number 179, 188, 211, 221, or 229 as disclosed in Table
 6. 16. The method according to any one of claims 13 through 15, wherein the method further comprises administering to the patient a second therapeutic agent.
 17. The method according to claim 16, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.
 18. A pharmacueitcal composition comprising any one or more of the isolated antibodies or antigen-binding fragments thereof of any one of claims 1 through 7 and a pharmaceutically acceptable carrier and/oror excipient.
 19. The pharmaceutical composition according to claim 18 for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSVinfection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
 20. The pharmaceutical composition according to claim 18 for us in treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
 21. Use of the pharmaceutical composition of claim 18 in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.
 22. Use of the pharmaceutical composition of claim 18 in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use. 